N-aryl-substituted cyclic amine derivative and medicine containing the same as active ingredient

ABSTRACT

The present invention provides an excellent squalene synthase inhibitor. Specifically, it provides a compound (I) represented by the following formula, a salt thereof or a hydrate of them.  
                 
 
     wherein R 1  represents an optionally substituted vinyl group or an aromatic ring which may be substituted;  
     n is an integer of 0 to 2;  
     X, Y and Z are the same as or different from each other and each represents an optionally substituted carbon atom, or an optionallysubstitutednitrogenatom, sulfuratomoroxygenatom, and Y optionally represents a single bond, and when Y represents the single bond, the ring to which X, Y and Z belong is a 5-membered ring;  
     CyA represents a 5- to 14 membered non-aromatic cyclic amino groupornon-aromatic cyclic amidogroupwhichmaybe substituted, and the non-aromatic cyclic amino group or the non-aromatic cyclic amido group optionally having an oxygen atom or a sulfur atom;  
     W represents a chain expressed by  
     (1) optionally substituted -CH 2 -CH 2 -,  
     (2) optionally substituted -CH=CH-,  
     (3) -C-C-,  
     (4) an optionally substituted phenylene group,  
     (5) a single bond,  
     (6) -NH-CO-,  
     (7) -CO-NH-,  
     (8) -NH-CH 2 -,  
     (9) -CH 2 -NH-,  
     (10) -CH 2 -CO-,  
     (11) -CO-CH 2 -,  
     (12) -O-(CH 2 ) m 1    
     (13) - (CH 2 ) -O- (where m represents an integer of 0 to 5),  
     (14) -O-CH 2 -CR 2 =1  
     (15) -O-CH 2 -CHR 2 - (where R 2  represents a hydrogen atom, a C 16  alkyl group or a halogen atom),  
     (16) -NH-S(O)l-,  
     (17) -S(O)3l-NH-,  
     (18) -CH 2 -S(°) 1 -. or  
     (19) -S(O),-CH 2 - (where 1 represents 0, 1, or 2); and  
     A represents a group having any of the following structural formulae:  
                 
 
     (wherein R 3  and R 4  represent independently a hydrogen atom or an optionally substituted C 16  alkyl group, or combine through a carbon chain optionally containing a heteroatom to form a ring;  
     R 5  and R 6  represent independently a hydrogen atom or an optionally substituted C 16  alkyl group, or combine through a carbon chain optionally containing a heteroatom to form a ring;  
     R 7  represents a hydrogen atom, an optionally substituted C 16  alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or an optionally substituted amino group;  
     R 8  represents a hydrogen atom, a hydroxyl group, an alkoxy group, a halogen atom or an optionally substituted amino group;  
     B1 represents an optionally substituted carbon atom, or an optionallysubstitutednitrogenatom, oxygenatomorsulfuratom;  
     B2 represents an optionally substituted carbon atom or nitrogen atom;  
     a and b represent an integer of 0 to 4, provided that a+b is an integer of 0 to 4;  
     c represents 0 or 1; and  
                 
 
     represents a single bond or a double bond, provided that when c is 1 in which A is a quinuclidine having R 8  represented by  
                 
 
     the case where R 8  is a hydrogen atom or a hydroxyl group; Arl is an aromatic heterocycle; and W is one of (1) to (3), (6) to (11) and (16) to (19) are excluded).

TECHNICAL FIELD

[0001] The present invention relates to a novel compound, a method forproducing the it, a squalene synthase inhibitor, a cholesterolbiosynthesis inhibitor and a triglyceride biosynthesis inhibitorcontaining such a novel compound and also to a medicinal compositioncontaining them. More specifically, the present invention relates topreventive and curative agents for hyperlipidemia including arterialsclerosis diseases and ischemic heart diseases.

PRIOR ART

[0002] Cholesterol is a sterol which is biosynthesized in all animalcells except for a red blood cell and is a substance essential formaintaining a plasma membrane and for the creation of a steroid hormone.Cholesterol is liposoluble and exists as low-density lipoprotein (LDL),high-density lipoprotein (HDL) and the like in blood. LDL in blood isincorporated into cells through a receptor on the surface of the cellsand regenerates free cholesterol after decomposed. This is a major routefor incorporating cholesterol from the outside of cells. Also, it hasbeen known that a major enzyme which participates in the biosynthesis ofLDL receptor protein and cholesterol undergoes feedback of theconcentration of cholesterol which is the harvested product. In thismanner, the level of cholesterol in cells is maintained and controlledexquisitely by the feedback control mechanism of the LDL receptor andbiosynthetic type enzyme on the basis of a balance between thebiosynthesis of a cell itself and the incorporation of LDL from theoutside of a cell.

[0003] The squalene synthase is a membrane-bound enzyme of 47-kDa andreducibly catalyzes the head-to-head condensation of two molecules ofFPP to synthesize squalene which is an intermediate for the synthesis ofcholesterol. In a cholesterol-biosynthesis system, the squalene synthaseis positioned downstream of a system generating the HMG-CoA reductaseand isoprene and therefore the squalene synthase inhibitor is consideredto have almost no effect on metabolic systems other than cholesterol andis therefore expected to work as a new cholesterol depressor which willsolve the problems concerning the HMG-CoA reductase inhibitor. Asqualene synthase inhibitor which was reported first is analogouscompounds of FPP and squalene. However, these analogous compounds has anactivity inhibiting the formation of prenyl protein and the like inaddition to squalene synthase inhibitive action and it is difficult toput these analogous compounds to practical use. In the meantime, it hasbeen disclosed recently that a certain type substitutedphenylethynylquinuclidine compound and substitutedpyridinylethynylquinuclidine compound are useful as a squalene synthaseinhibitor in JP-A 7-502283, 8-502731, 8-504803 (U.S. Pat. No. 5,731,323)and 8-509488. However, no squalene synthase inhibitor which can producean effect as a medicine for hyperlipidemia has been created so far.

[0004] That is, an object of the present invention is to search and tofind a compound which has stronger squalene synthase inhibitiveactivities and cholesterol depressing action over those currently in useand is useful as a remedy for hyperlipidemia.

DISCLOSURE OF THE INVENTION

[0005] In view of the above situation, the inventors of the presentinvention have made earnest studies and as a result, found that aspecific quinuclidine compound and its salt have unprecedented strongsqualene synthase inhibitive activities. The inventors have also foundthat these compounds and their salts have strong cholesterolbiosynthesis inhibitive activities, triglyceride biosynthesis inhibitiveactivities and serum cholesterol depressing action and serumtriglyceride depressing action based on the inhibition of squalenesynthase. The present invention has been thus completed. A compoundaccording to the present invention is useful as a remedy forhyperlipidemia.

[0006] The present invention is a compound (I) represented by theformula:

[0007] (wherein R¹ represents an optionally substituted vinyl group oran aromatic ring which may be substituted;

[0008] n is an integer of 0 to 2;

[0009] X, Y, and Z are the same as or different from each other and eachrepresents an optionally substituted carbon atom, or an optionallysubstituted nitrogen atom, sulfur atom or oxygen atom, and Y mayrepresent a single bond and when Y represents the single bond, the ringto which X, Y and Z belong is a 5-membered;

[0010] CyA represents a 5- to 14 membered non-aromatic cyclic aminogroup or non-aromatic cyclic amido group, each of which may besubstituted, and the non-aromatic cyclic amino group or the non-aromaticcyclic amido group may contain an oxygen atom or a sulfur atom;

[0011] W represents a chain expressed by

[0012] (1) optionally substituted —CH₂—CH₂—,

[0013] (2) optionally substituted —CH═CH—,

[0014] (3) —C≡C—,

[0015] (4) an optionally substituted phenylene group,

[0016] (5) a single bond,

[0017] (6) —NH—CO—,

[0018] (7) —CO—NH—,

[0019] (8) —NH—CH₂—,

[0020] (9) —CH₂—NH—,

[0021] (10) —CH₂—CO—,

[0022] (11) —CO—CH₂—,

[0023] (12) —O—(CH₂)_(m)—,

[0024] (13) —(CH₂)_(m)—O— (where m represents an integer of 0 to 5),

[0025] (14) —O—CH₂—CR²═,

[0026] (15) —O—CH₂—CHR²— (where R² represents a hydrogen atom, a C₁₆alkyl group, or a halogen atom),

[0027] (16) —NH—S(O)₁—,

[0028] (17) —S(O)₁—NH—,

[0029] (18) —CH₂—S(O)₁— or

[0030] (19) —S(O)₁—CH₂— (where 1 represents 0, 1, or 2); and

[0031] A represents a group having any of the following structuralformulae:

[0032]  (wherein R³ and R⁴ are independent of each other and eachrepresents a hydrogen atom or an optionally substituted C₁-₆ alkylgroup, or combine through a carbon chain optionally containing aheteroatom to form a ring;

[0033] R⁵ and R⁶are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring;

[0034] R⁷ represents a hydrogen atom, an optionally substituted C₁₋₆alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or anoptionally substituted amino group;

[0035] R⁸ represents a hydrogen atom, a hydroxyl group, an alkoxy group,a halogen atom or an optionally substituted amino group,

[0036] B¹ represents an optionally substituted carbon atom, or anoptionally substituted nitrogen atom, oxygen atom or sulfur atom;

[0037] B² represents an optionally substituted carbon atom or nitrogenatom;

[0038] a and b represent an integer of 0 to 4, provided that a+b is aninteger of 0 to 4,

[0039] c represents 0 or 1; and

[0040]  represents a single bond or a double bond, provided that when cis 1 in which A is a quinuclidine having R⁸ represented by

[0041]  the case where R⁸ is a hydrogen atom or a hydroxyl group; Arl isan aromatic heterocycle; and W is one of (1) to (3), (6) to (11) and(16) to (19) are excluded)), a salt thereof or a hydrate of them.

[0042] The present invention is a compound, in the above-mentionedcompound (I), R¹ represents an optionally substituted vinyl group, abenzene ring which may be substituted or a thiophene ring which may besubstituted;

[0043] n is an integer of 0 to 2;

[0044] Arl represents a benzene ring, pyridine ring, pyrimidine ring,pyrazine ring, pyridazine ring, triazine ring, thiazole ring, thiophenering, pyrrole ring or furan ring, each of which may be substituted witha lower alkyl group, a halogen atom or an alkoxy group;

[0045] CyA represents an azetidine ring, pyrrolidine ring, piperidinering, piperazine ring, morpholine ring, 2-azetidinone ring,2-pyrrolidinone ring, 2-piperidinone ring, 2-piperazinone ring or3-morpholine ring, each of which may be substituted with one to threegroups which are the same as or different from each other selected from:

[0046] (1) a lower alkyl group which may be substituted,

[0047] (2) a lower alkenyl group which may be substituted,

[0048] (3) a lower alkynyl group which may be substituted,

[0049] (4) a lower alkoxy group which may be substituted,

[0050] (5) an oxo group,

[0051] (6) a nitrile group,

[0052] (7) an alkylenedioxy group,

[0053] (8) a hydroxyl group,

[0054] (9) a halogen atom,

[0055] (10) an amino group which may be substituted,

[0056] (11) an acylamino group,

[0057] (12) a carbamoyl group which may be substituted,

[0058] (13) a carbamoyloxy group which may be substituted,

[0059] (14) a carboxyl group,

[0060] (15) an acyl group,

[0061] (16) an acyloxy group, and

[0062] (17) an alkoxycarbonyloxy group;

[0063] W represents a chain expressed by

[0064] (1) optionally substituted —CH₂—CH₂—,

[0065] (2) optionally substituted —CH═CH—,

[0066] (3) —C≡C—,

[0067] (4) an optionally substituted phenylene group,

[0068] (5) a single bond,

[0069] (6) —NH—CO—,

[0070] (7) —CO—NH—,

[0071] (8) —NH—CH₂—,

[0072] (9) —CH₂—NH—,

[0073] (10) —CH₂—CO—,

[0074] (11) —CO—CH₂—,

[0075] (12) —O—(CH₂)_(m)—,

[0076] (13) —(CH₂)_(m)—O— (where m represents an integer of 0 to 5),

[0077] (14) —O—CH₂—CR²═,

[0078] (15) —O—CH₂—CHR— (where R² represents a hydrogen atom, a C₁₋₆alkyl group, or a halogen atom),

[0079] (16) —NH—S(O)₁—,

[0080] (17) —S(O)₁—NH—,

[0081] (18) —CH₂—S(O)₁— or

[0082] (19) —S(O)₁—CH₂— (where 1 represents 0, 1, or 2); and

[0083] A represents a group having any of the following structuralformulae:

[0084]  (wherein R³ and R⁴ are independent of each other and eachrepresents a hydrogen atom or an optionally substituted C₁₋₆alkyl group,or combine through a carbon chain optionally containing a heteroatom toform a ring;

[0085] R⁵ and R⁶ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring;

[0086] R⁷ represents a hydrogen atom, an optionally substituted C₁₋₆alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or anoptionally substituted amino group;

[0087] R⁸ represents a hydrogen atom, a hydroxyl group, an alkoxy group,a halogen atom or an optionally substituted amino group,

[0088] B¹ represents an optionally substituted carbon atom, or anoptionally substituted nitrogen atom, oxygen atom or sulfur atom;

[0089] B² represents an optionally substituted carbon atom or nitrogenatom;

[0090] a and b represent an integer of 0 to 4, provided that a+b is aninteger of 0 to 4,

[0091] c represents 0 or 1; and

[0092]  represents a single bond or a double bond, provided that when cis 1 in which A is a quinuclidine having R⁸ represented by

[0093]  the case where R⁸ is a hydrogen atom or a hydroxyl group; Arl isan aromatic heterocycle; and W is one of (1) to (3), (6) to (11) and(16) to (19) are excluded), a salt thereof or a hydrate of them.

[0094] The present invention is also a compound, in the above-mentionedcompound (I), Arl preferably represents a benzene ring, pyridine ring,pyrimidine ring or thiazole ring optionally substituted with a loweralkyl group, a halogen atom or an alkoxy group;

[0095] R¹ represents an optionally substituted vinyl group, a benzenering which may be substituted or a thiophene ring which may besubstituted;

[0096] n is an integer of 0 to 2;

[0097] CyA represents an azetidine ring, pyrrolidine ring, piperidinering, piperazine ring, morpholine ring, 2-azetidinone ring,2-pyrrolidinone ring, 2-piperidinone ring, 2-piperazinone ring or3-morpholine ring, each of which may be substituted with one to threegroups which are the same as or different from each other selected from:

[0098] (1) a lower alkyl group which may be substituted,

[0099] (2) a lower alkenyl group which may be substituted,

[0100] (3) a lower alkynyl group which may be substituted,

[0101] (4) a lower alkoxy group which may be substituted,

[0102] (5) an oxo group,

[0103] (6) a nitrile group,

[0104] (7) an alkylenedioxy group,

[0105] (8) a hydroxyl group,

[0106] (9) a halogen atom,

[0107] (10) an amino group which may be substituted,

[0108] (11) an acylamino group,

[0109] (12) a carbamoyl group which may be substituted,

[0110] (13) a carbamoyloxy group which may be substituted,

[0111] (14) a carboxyl group,

[0112] (15) an acyl group,

[0113] (16) an acyloxy group, and

[0114] (17) an alkoxycarbonyloxy group;

[0115] W represents a chain expressed by

[0116] (1) optionally substituted —CH₂—CH₂—,

[0117] (2) optionally substituted —CH═CH—,

[0118] (3) —C≡C—,

[0119] (4) an optionally substituted phenylene group,

[0120] (5) a single bond,

[0121] (6) —NH—CO—,

[0122] (7) —CO—NH—,

[0123] (8) —NH—CH₂—,

[0124] (9) —CH₂—NH—,

[0125] (10) —CH₂—CO—,

[0126] (11) —CO—CH₂—,

[0127] (12) —O—(CH₂)_(m)—,

[0128] (13) —(CH₂)_(m)—O— (where m represents an integer of 0 to 5),

[0129] (14) —O—CH₂—CR²≡,

[0130] (15) —O—CH₂—CHR— (where R² represents a hydrogen atom, a C₁₋₆alkyl group, or a halogen atom),

[0131] (16) —NH—S(O)₁—,

[0132] (17) —S(O)₁—NH—,

[0133] (18) —CH₂—S(O)₁— or

[0134] (19) —S(O)₁—CH₂— (where 1 represents 0, 1, or 2); and

[0135] A represents a group having any of the following structuralformulae:

[0136]  (wherein R³ and R⁴ are independent of each other and eachrepresents a hydrogen atom or an optionally substituted C₁₋₆ alkylgroup, or combine through a carbon chain optionally containing aheteroatom to form a ring;

[0137] R⁵ and R⁶ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring;

[0138] R⁷ represents a hydrogen atom, an optionally substituted C₁₋₆alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or anoptionally substituted amino group;

[0139] R⁸ represents a hydrogen atom, a hydroxyl group, an alkoxy group,a halogen atom or an optionally substituted amino group,

[0140] B¹ represents an optionally substituted carbon atom, or anoptionally substituted nitrogen atom, oxygen atom or sulfur atom;

[0141] B² represents an optionally substituted carbon atom or nitrogenatom;

[0142] a and b represent an integer of 0 to 4, provided that a+b is aninteger of 0 to 4,

[0143] c represents 0 or 1; and

[0144]  represents a single bond or a double bond, provided that when cis 1 in which A is a quinuclidine having R⁸ represented by

[0145]  the case where R⁸ is a hydrogen atom or a hydroxyl group; Arl isan aromatic heterocycle; and W is one of (1) to (3), (6) to (11) and(16) to (19) are excluded), a salt thereof or a hydrate of them.

[0146] Further, the present invention is a compound, in theabove-mentioned compound (I), W preferably represents a chain expressedby

[0147] (1) optionally substituted —CH₂—CH₂—,

[0148] (2) optionally substituted —CH═CH—,

[0149] (3) —C≡C—,

[0150] (4) an optionally substituted phenylene group,

[0151] (5) a single bond,

[0152] (13) —(CH₂)_(m)—O— (where m represents an integer of 0 to 5),

[0153] (14) —O—CH₂—CR²═, or

[0154] (15) —O—CH₂—CHR — (where R² represents a hydrogen atom, an alkylgroup or a halogen atom);

[0155] R¹ represents an optionally substituted vinyl group, a benzenering which may be substituted or a thiophene ring which may besubstituted;

[0156] n is an integer of 0 to 2;

[0157] Arl represents a benzene ring, pyridine ring, pyrimidine ring,pyrazine ring, pyridazine ring, triazine ring, thiazole ring, thiophenering, pyrrole ring or furan ring, each of which may be substituted witha lower alkyl group, a halogen atom or an alkoxy group;

[0158] CyA represents an azetidine ring, pyrrolidine ring, piperidinering, piperazine ring, morpholine ring, 2-azetidinone ring,2-pyrrolidinone ring, 2-piperidinone ring, 2-piperazinone ring or3-morpholine ring, each of which may be substituted with one to threegroups which are the same as or different from each other selected from:

[0159] (1) a lower alkyl group which may be substituted,

[0160] (2) a lower alkenyl group which may be substituted,

[0161] (3) a lower alkynyl group which may be substituted,

[0162] (4) a lower alkoxy group which may be substituted,

[0163] (5) an oxo group,

[0164] (6) a nitrile group,

[0165] (7) an alkylenedioxy group,

[0166] (8) a hydroxyl group,

[0167] (9) a halogen atom,

[0168] (10) an amino group which may be substituted,

[0169] (11) an acylamino group,

[0170] (12) a carbamoyl group which may be substituted,

[0171] (13) a carbamoyloxy group which may be substituted,

[0172] (14) a carboxyl group,

[0173] (15) an acyl group,

[0174] (16) an acyloxy group,

[0175] (17) an alkoxycarbonyloxy group; and

[0176] A represents a group having any of the following structuralformulae:

[0177]  (wherein R³ and R⁴ are independent of each other and eachrepresents a hydrogen atom or an optionally substituted C₁₋₆ alkylgroup, or combine through a carbon chain optionally containing aheteroatom to form a ring;

[0178] R⁵ and R⁶ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring;

[0179] R⁷ represents a hydrogen atom, an optionally substituted C₁₋₆alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or anoptionally substituted amino group;

[0180] R⁸ represents a hydrogen atom, a hydroxyl group, an alkoxy group,a halogen atom or an optionally substituted amino group,

[0181] B¹ represents an optionally substituted carbon atom, or anoptionally substituted nitrogen atom, oxygen atom or sulfur atom;

[0182] B² represents an optionally substituted carbon atom or nitrogenatom;

[0183] a and b represent an integer of 0 to 4, provided that a+b is aninteger of 0 to 4,

[0184] c represents 0 or 1; and

[0185]  represents a single bond or a double bond, provided that when cis 1 in which A is a quinuclidine having R⁸ represented by

[0186]  the case where R⁸ is a hydrogen atom or a hydroxyl group; Arl isan aromatic heterocycle; and W is one of (1) to (3), (6) to (11) and(16) to (19) are excluded), a salt thereof or a hydrate of them.

[0187] Also, the present invention is a compound, in the above-mentionedcompound (I), Arl preferably represents a benzene ring, pyridine ring,pyrimidine ring or thiazole ring, each of which may be substituted witha lower alkyl group, a halogen atom or an alkoxy group;

[0188] W preferably represents a chain expressed by

[0189] (1) optionally substituted —CH₂—CH₂—,

[0190] (2) optionally substituted —CH═CH—,

[0191] (3) —C≡C—,

[0192] (4) an optionally substituted phenylene group,

[0193] (5) a single bond,

[0194] (13) —(CH₂)_(m)—O— (where m represents an integer of 0 to 5),

[0195] (14) —O—CH₂—CR²═, or

[0196] (15) —O—CH₂—CHR²— (where R² represents a hydrogen atom, an alkylgroup or a halogen atom);

[0197] R¹ represents an optionally substituted vinyl group, a benzenering which may be substituted or a thiophene ring which may besubstituted;

[0198] n is an integer of 0 to 2;

[0199] CyA represents an azetidine ring, pyrrolidine ring, piperidinering, piperazine ring, morpholine ring, 2-azetidinone ring,2-pyrrolidinone ring, 2-piperidinone ring, 2-piperazinone ring or3-morpholine ring, each of which may be substituted with one to threegroups which are the same as or different from each other and selectedfrom:

[0200] (1) a lower alkyl group which may be substituted,

[0201] (2) a lower alkenyl group which may be substituted,

[0202] (3) a lower alkynyl group which may be substituted,

[0203] (4) a lower alkoxy group which may be substituted,

[0204] (5) an oxo group,

[0205] (6) a nitrile group,

[0206] (7) an alkylenedioxy group,

[0207] (8) a hydroxyl group,

[0208] (9) a halogen atom,

[0209] (10) an amino group which may be substituted,

[0210] (11) an acylamino group,

[0211] (12) a carbamoyl group which may be substituted,

[0212] (13) a carbamoyloxy group which may be substituted,

[0213] (14) a carboxyl group,

[0214] (15) an acyl group,

[0215] (16) an acyloxy group, and

[0216] (17) an alkoxycarbonyloxy group; and

[0217] A represents a group having any of the following structuralformulae:

[0218]  (wherein R³ and R⁴ are independent of each other and eachrepresents a hydrogen atom or an optionally substituted C₁₋₆ alkylgroup, or combine through a carbon chain optionally containing aheteroatom to form a ring;

[0219] R⁵ and R⁶ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring;

[0220] R⁷ represents a hydrogen atom, an optionally substituted C₁₋₆alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or anoptionally substituted amino group;

[0221] R⁸ represents a hydrogen atom, a hydroxyl group, an alkoxy group,a halogen atom or an optionally substituted amino group,

[0222] B¹ represents an optionally substituted carbon atom, or anoptionally substituted nitrogen atom, oxygen atom or sulfur atom;

[0223] B² represents an optionally substituted carbon atom or nitrogenatom;

[0224] a and b represent an integer of 0 to 4, provided that a+b is aninteger of 0 to 4,

[0225] c represents 0 or 1; and

[0226]  represents a single bond or a double bond, provided that when cis 1 in which A is a quinuclidine having R⁸ represented by

[0227]  the case where R⁸ is a hydrogen atom or a hydroxyl group; Arl isan aromatic heterocycle; and W is one of (1) to (3), (6) to (11) and(16) to (19) are excluded), a salt thereof or a hydrate of them.

[0228] Also, the present invention is a compound, in the above-mentionedcompound (I), Arl preferably represents a benzene ring, pyridine ring,pyrimidine ring or thiazole ring, each of which may be substituted witha lower alkyl group, a halogen atom or an alkoxy group;

[0229] W preferably represents a chain expressed by

[0230] (1) optionally substituted —CH₂—CH₂—,

[0231] (2) optionally substituted —CH═CH—,

[0232] (3) —C≡C—,

[0233] (4) an optionally substituted phenylene group,

[0234] (5) a single bond,

[0235] (13) —(CH₂)_(m)—O— (where m represents an integer of 0 to 5),

[0236] (14) —O—CH₂—CR²═, or

[0237] (15) —O—CH₂—CHR²— (where R² represents a hydrogen atom, an alkylgroup or a halogen atom);

[0238] CyA preferably represents an azetidine ring, pyrrolidine ring,piperidine ring, piperazine ring, morpholine ring, 2-azetidinone ring,2-pyrrolidinone ring, 2-piperidinone ring, 2-piperazinone ring or3-morpholine ring, each of which may be substituted with one to threegroups which are the same as or different from each other selected from:

[0239] (1) a lower alkyl group which may be substituted,

[0240] (4) a lower alkoxy group which may be substituted,

[0241] (5) an oxo group,

[0242] (7) an alkylenedioxy group,

[0243] (8) a hydroxyl group, and

[0244] (9) a halogen atom;

[0245] R¹ represents an optionally substituted vinyl group, a benzenering which may be substituted or a thiophene ring which may besubstituted;

[0246] n is an integer of 0 to 2; and

[0247] A represents a group having any of the following structuralformulae:

[0248]  (wherein R³ and R⁴ are independent of each other and eachrepresents a hydrogen atom or an optionally substituted C₁₋₆ alkylgroup, or combine through a carbon chain optionally containing aheteroatom to form a ring;

[0249] R⁵ and R⁶ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring;

[0250] R⁷ represents a hydrogen atom, an optionally substituted C₁₋₆alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or anoptionally substituted amino group;

[0251] R⁸ represents a hydrogen atom, a hydroxyl group, an alkoxy group,a halogen atom or an optionally substituted amino group,

[0252] B¹ represents an optionally substituted carbon atom, or anoptionally substituted nitrogen atom, oxygen atom or sulfur atom;

[0253] B² represents an optionally substituted carbon atom or nitrogenatom;

[0254] a and b represent an integer of 0 to 4, provided that a+b is aninteger of 0 to 4,

[0255] c represents 0 or 1; and

[0256]  represents a single bond or a double bond, provided that when cis 1 in which A is a quinuclidine having R⁸ represented by

[0257]  the case where R⁸ is a hydrogen atom or a hydroxyl group; Arl isan aromatic heterocycle; and W is one of (1) to (3), (6) to (11) and(16) to (19) are excluded), a salt thereof or a hydrate of them.

[0258] Also, the present invention is a compound, in the above-mentionedcompound (I), Arl preferably represents a benzene ring, pyridine ring,pyrimidine ring or thiazole ring, each of which may be substituted witha lower alkyl group, a halogen atom or an alkoxy group;

[0259] W preferably represents a chain expressed by

[0260] (1) optionally substituted —CH₂—CH₂—,

[0261] (2) optionally substituted —CH═CH—,

[0262] (3) —C≡C—,

[0263] (4) an optionally substituted phenylene group,

[0264] (5) a single bond,

[0265] (13) —(CH₂)_(m)—O— (where m represents an integer of 0 to 5),

[0266] (14) —O—CH₂—CR²═, or

[0267] (15) —O—CH₂—CHR²— (where R² represents a hydrogen atom, an alkylgroup or a halogen atom);

[0268] CyA represents an azetidine ring, pyrrolidine ring, piperidinering, piperazine ring, morpholine ring, 2-azetidinone ring,2-pyrrolidinone ring, 2-piperidinone ring, 2-piperazinone ring or3-morpholine ring, each of which may be substituted with one to threegroups which are the same as or different from each other and selectedfrom:

[0269] (1) a lower alkyl group which may be substituted,

[0270] (4) a lower alkoxy group which may be substituted,

[0271] (5) an oxo group,

[0272] (7) an alkylenedioxy group,

[0273] (8) a hydroxyl group, and

[0274] (9) a halogen atom;

[0275] R¹ represents a benzene ring which may be substituted;

[0276] n is an integer of 0 to 2; and

[0277] A represents a group having any of the following structuralformulae:

[0278]  (wherein R³ and R⁴ are independent of each other and eachrepresents a hydrogen atom or an optionally substituted C₁₋₆ alkylgroup, or combine through a carbon chain optionally containing aheteroatom to form a ring;

[0279] R⁵ and R⁶are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring;

[0280] R⁷ represents a hydrogen atom, an optionally substituted C₁₋₆alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or anoptionally substituted amino group;

[0281] R⁸ represents a hydrogen atom, a hydroxyl group, an alkoxy group,a halogen atom or an optionally substituted amino group,

[0282] B¹ represents an optionally substituted carbon atom, or anoptionally substituted nitrogen atom, oxygen atom or sulfur atom;

[0283] B² represents an optionally substituted carbon atom or nitrogenatom;

[0284] a and b represent an integer of 0 to 4, provided that a+b is aninteger of 0 to 4,

[0285] c represents 0 or 1; and

[0286]  represents a single bond or a double bond, provided that when cis 1 in which A is a quinuclidine having R⁸ represented by

[0287]  the case where R⁸ is a hydrogen atom or a hydroxyl group; Arl isan aromatic heterocycle; and W is one of (1) to (3), (6) to (11) and(16) to (19) are excluded) a salt thereof or a hydrate of them.

[0288] The present invention is a compound selected from the groupconsisting of:

[0289]3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynyl-3-piperidinol;

[0290]3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynyl-1-methyl-3-piperidinol;

[0291]4-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]-1-methyl-4-piperidinol;

[0292]4-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]-1-methyl-1,2,3,6-tetradydropyridine;

[0293]3-[3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]propyloxy]pyrrolidine;

[0294]1-[2-benzyl-6-[(3R,4S)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynylcyclohexylamine;

[0295]1-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynylcyclohexylamine;

[0296]1-[2-benzyl-6-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinon-1-y1]-3-pyridyl]ethynylcyclohexylamine;

[0297]1-[2-benzyl-6-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinon-1-yl]-3-pyridyl)ethynylcyclohexylamine;

[0298]1-[1-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl)-3-pyridyl]ethynylcyclohexyl]piperidine;

[0299]1-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl)ethynyl-N-methycyclohexylamine;

[0300]2-[[1-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynylcyclohexyl]amino]ethanol;

[0301]3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]-1,1-diethyl-2-propynylamine;

[0302]2-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynylbicyclo[2.21]heptan-2ol;

[0303](3R)-3-[2-benzyl-4-(2-pyrrolidinon-1-yl)phenyl]ethynyl-3-quinuclidinol;

[0304](3R)-3-[2-benzyl-4-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinon-1-yl)phenyl]ethylnyl-3-quinuclidinol;

[0305](3R)-3-[2-benzyl-4-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinon-1-yl]phenyl]ethynyl-3-quinuclidinol;

[0306](3R)-3-[2-benzyl-4-[(3R,4S)-3,4-dimethoxypyrrolidin-1-yl)phenyl]ethynyl-3-quinuclidinol;

[0307](3R)-3-[2-benzyl-4-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]phenyl]ethynyl-3-quinuclidinol;

[0308](3R)-3-[2-benzyl-4-[cis-3-hydroxy-4-methoxypyrrolidin-1-yl]phenyl]ethynyl-3-quinuclidinol;

[0309](3R)-3-[2-benzyl-4-[trans-3-hydroxy-4-methoxypyrrolidin-1-yl]phenyl]ethynyl-3-quinuclidinol;

[0310]3-[4-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl)-3-pyridyl]phenyl]-3-quinuclidinol;

[0311](E)-3-[2-[2-benzyl-6-(2-pyrrolidinon-1-yl)pyridin-3-yloxy]-1-fluoroethynylidene]quinuclidine;

[0312]1-[2-benzyl-6-(3,3-ethylenedioxypyrrolidin-1-yl]-3-pyridyl]ethynylcyclohexylamine;

[0313]1-[2-benzyl-6-(4-methoxypiperidino)-3-pyridyl]ethynylcyclohexylamine;

[0314]4-[2-benzyl-6-[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]-3pyridyl]ethynyl-exo-1-azaadamantan-4-ol;and

[0315]4-[2-benzyl-6-[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]-3-pyridyl]ethynyl-endo-1-azaadamantan-4-ol.

[0316] Also, the present invention is a pharmaceutical compositioncomprising a compound (I) represented by the formula:

[0317] (wherein R¹ represents an optionally substituted vinyl group oran aromatic ring which may be substituted;

[0318] n is an integer of 0 to 2;

[0319] X, Y, and Z are the same as or different from each other and eachrepresents an optionally substituted carbon atom, or an optionallysubstituted nitrogen atom, sulfur atom or oxygen atom, and Y mayrepresent a single bond and when Y represents the single bond, the ringto which X, Y and Z belong is a 5-membered;

[0320] CyA represents a 5- to 14 membered non-aromatic cyclic aminogroup or non-aromatic cyclic amido group, each of which may besubstituted, and the non-aromatic cyclic amino group or the non-aromaticcyclic amido group may contain an oxygen atom or a sulfur atom;

[0321] W represents a chain expressed by

[0322] (1) optionally substituted —CH₂—CH₂—,

[0323] (2) optionally substituted —CH═CH—,

[0324] (3) —C≡C—,

[0325] (4) an optionally substituted phenylene group,

[0326] (5) a single bond,

[0327] (6) —NH—CO—,

[0328] (7) —CO—NH—,

[0329] (8) —NH—CH₂—,

[0330] (9) —CH₂—NH—,

[0331] (10) —CH₂—CO—,

[0332] (11) —CO—CH₂—,

[0333] (12) —O—(CH₂)_(m)—,

[0334] (13) —(CH₂)_(m)—O— (where m represents an integer of 0 to 5),

[0335] (14) —O—CH₂—CR²═,

[0336] (15) —O—CH₂—CHR²— (where R² represents a hydrogen atom, a C₁₋₆alkyl group, or a halogen atom),

[0337] (16) —NH—S(O)₁—,

[0338] (17) —S(O)₁—NH—,

[0339] (18) —CH₂—S(O)₁— or

[0340] (19) —S(O)₁—CH₂— (where 1 represents 0, 1, or 2); and

[0341] A represents a group having any of the following structuralformulae:

[0342]  (wherein R³ and R⁴ are independent of each other and eachrepresents a hydrogen atom or an optionally substituted C₁₋₆ alkylgroup, or combine through a carbon chain optionally containing aheteroatom to form a ring;

[0343] R⁵ and R⁶ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring;

[0344] R⁷ represents a hydrogen atom, an optionally substituted C₁₋₆alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or anoptionally substituted amino group;

[0345] R⁸ represents a hydrogen atom, a hydroxyl group, an alkoxy group,a halogen atom or an optionally substituted amino group,

[0346] B¹ represents an optionally substituted carbon atom, or anoptionally substituted nitrogen atom, oxygen atom or sulfur atom;

[0347] B² represents an optionally substituted carbon atom or nitrogenatom;

[0348] a and b represent an integer of 0 to 4, provided that a+b is aninteger of 0 to 4,

[0349] c represents 0 or 1; and

[0350]  represents a single bond or a double bond, provided that when cis 1 in which A is a quinuclidine having R⁸represented by

[0351]  the case where R⁸ is a hydrogen atom or a hydroxyl group; Arl isan aromatic heterocycle; and W is one of (1) to (3), (6) to (11) and(16) to (19) are excluded)), a salt thereof or a hydrate of them, and apreparation carrier.

[0352] The present invention is a pharmaceutical composition comprisingthe above-mentioned compound (I), a salt thereof or a hydrate of them,as an agent for preventing or treating a disease against which squalenesynthase inhibition is efficacious.

[0353] The present invention is a cholesterol biosynthesis inhibitorcomprising the above-mentioned compound (I), a salt thereof or a hydrateof them.

[0354] The present invention is a triglyceride biosynthesis inhibitorcomprising the above-mentioned compound (I), a salt thereof or a hydrateof them.

[0355] The present invention is an agent for preventing or treatinghyperlipidemia, which comprises the above-mentioned compound (I), a saltthereof or a hydrate of them.

[0356] The present invention is an agent for preventing or treatingarterial sclerosis diseases or ischemic heart diseases, which comprisesthe above-mentioned compound (I), a salt thereof or a hydrate of them.

[0357] The present invention is an agent for preventing or treatinghypertension, coronary diseases, cerebrovascular diseases, aorticdiseases, peripheral arterial diseases, angina pectoris, acute coronarysyndromes or cardiac infarction, which comprises the above-mentionedcompound (I), a salt thereof or a hydrate of them.

[0358] The present invention provides a method of preventing or treatinga disease against which squalene synthase inhibition is efficacious, byadministering a pharmaceutically effective amount of the above-mentionedcompound (I), a salt thereof or a hydrate of the to a patient.

[0359] Also, the present invention provides use of the above-mentionedcompound (I), a salt thereof or a hydrate of the, for producing an agentfor preventing or treating a disease against which squalene synthaseinhibition is efficacious.

[0360] Further, the present invention provides a method of preventing ortreating a disease against which cholesterol biosynthesis inhibition isefficacious, a disease against which triglyceride biosynthesisinhibition is efficacious, hyperlipidemia, arterial sclerosis diseases,ischemic heart diseases, hypertension, coronary diseases,cerebrovascular diseases, aortic diseases, peripheral arterial diseases,angina pectoris, acute coronary syndromes or cardiac infarction, byadministering a pharmaceutically effective amount of the above-mentionedcompound (I), a salt thereof or a hydrate of the to a patient.

[0361] Furthermore, the present invention provides use of theabove-mentioned compound (I), a salt thereof or a hydrate of the, forproducing an agent for preventing or treating a disease against whichcholesterol biosynthesis inhibition is efficacious, a disease againstwhich triglyceride biosynthesis inhibition is efficacious,hyperlipidemia, arterial sclerosis diseases, ischemic heart diseases,hypertension, coronary diseases, cerebrovascular diseases, aorticdiseases, peripheral arterial diseases, angina pectoris, acute coronarysyndromes or cardiac infarction.

[0362] In the specification of the present invention, there is the casewhere the structural formula of a compound represents a definite isomer.However, the present invention includes isomers such as geometricalisomers, optical isomers based on asymmetric carbon, stereoisomers andtautomers and is not limited by the description of the formulaillustrated for the sake of convenience.

[0363] Hereinafter, the terms used in the present specification will bedefined.

[0364] In the present specification, the group represented by R¹ in thegeneral formula (I) means an optionally substituted vinyl group or anaromatic ring which may be substituted, preferably an aromatic ringwhich may be substituted. Here, the aromatic ring is not particularlylimited and means, for example, a benzene ring, a thiophene ring, etc.On the other hand, the optionally substituted vinyl group means that onehydrogen atom or more in the vinyl group may be substituted by, forexample, an optionally protected hydroxyl group, a halogen atom, anitrile group, a carboxyl group, a C₁₋₆ alkyl group, or the like. Agroup “optionally substituted” means that the group may have one or moresubstituent(s) such as, for example, a hydroxyl group which may beprotected, a halogen atom, a nitrile group, a carboxyl group, or a C₁₋₆alkyl group.

[0365] Further, an “optionally substituted” group in the definitions ofX, Y and Z means that the group may be substituted with, for example, alower alkyl group, a halogen atom or a lower alkoxy group. CyA in thegeneral formula (I) represents a 5- to 14-membered non-aromatic cyclicamino group which may be substituted; the aromatic cyclic amino groupoptionally contains an oxygen atom or a sulfur atom. For example, anazetidine ring, a pyrrolidine ring, a piperidine ring, a piperazinering, a morpholine ring, etc. may be proposed, and a pyrrolidine ring isparticularly preferred. A group “which may be substituted” in CyAincludes, for example,

[0366] (1) a lower alkyl group which may be substituted,

[0367] (2) a lower alkenyl group which may be substituted,

[0368] (3) a lower alkynyl group which may be substituted,

[0369] (4) a lower alkoxy group which may be substituted,

[0370] (5) an oxo group,

[0371] (6) a nitrile group,

[0372] (7) an alkylenedioxy group,

[0373] (8) a hydroxyl group,

[0374] (9) a halogen atom,

[0375] (10) an amino group which may be substituted,

[0376] (11) an acylamino group,

[0377] (12) a carbamoyl group which may be substituted,

[0378] (13) a carbamoyloxy group which may be substituted,

[0379] (14) a carboxyl group,

[0380] (15) an acyl group,

[0381] (16) an acyloxy group, and

[0382] (17) an alkoxycarbonyloxy group.

[0383] W represents a bonding chain whose main chain is constituted bytwo or more atoms, and preferably includes chains represented by, forexample,

[0384] (1) optionally substituted —CH₂—CH₂—,

[0385] (2) optionally substituted —CH═CH—,

[0386] (3) —C≡C—,

[0387] (4) an optionally substituted phenylene group,

[0388] (5) a single bond,

[0389] (6) —NH—CO—,

[0390] (7) —CO—NH—,

[0391] (8) —NH—CH₂—,

[0392] (9) —CH₂—NH—,

[0393] (10) —CH₂—CO—,

[0394] (11) —CO—CH₂—,

[0395] (12) —O—(CH₂)_(m)—,

[0396] (13) —(CH₂)_(m)—O— (where m represents an integer of 0 to 5),

[0397] (14) —O—CH₂—CR²═,

[0398] (15) —O—CH₂—CHR²— (where R² represents a hydrogen atom, a C₁₋₆alkyl group or a halogen atom),

[0399] (16) —NH—S(O)₁—,

[0400] (17) —S(O)₁—NH—,

[0401] (18) —CH₂—S(O)₁—, or

[0402] (19) —S(O)₁—CH₂— (where 1 represents 0, 1, or 2), morepreferably,

[0403] (1) —CH₂—CH₂—,

[0404] (2) —CH═CH—, or

[0405] (3) —C≡C—, still more preferably, —C≡C—.

[0406] Here, “optionally substituted —CH₂—CH₂—” and “optionallysubstituted —CH═CH—” mean that one hydrogen atom or more in the—CH₂—CH₂— or —CH═CH— may be substituted by, for example, an optionallyprotected hydroxyl group, a halogen atom, a nitrile group, a carboxylgroup or a C₁₋₆ alkyl group.

[0407] A represents:

[0408] wherein, R³ and R⁴ are independent of each other and eachrepresents a hydrogen atom or an optionally substituted C₁₋₆ alkylgroup, or combine through a carbon chain optionally containing aheteroatom to form a ring; R⁵ and R⁶ are independent of each other andeach represents a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, ahydroxyl group or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring; R⁷ represents a hydrogen atom, an optionally substituted C₁₋₆alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or anoptionally substituted amino group; R⁸ represents a hydrogen atom, ahydroxyl group, an alkoxy group, a halogen atom or an optionallysubstituted amino group; B¹ represents an optionally substituted carbonatom, or an optionally substituted nitrogen atom, oxygen atom or sulfuratom; B² represents an optionally substituted carbon atom or nitrogenatom; and

[0409] represents a single bond or a double bond.

[0410] In the definitions of R³ to R⁸, “optionally substituted C₁₋₆alkyl group” means a C₁₋₆ alkyl group which may be substituted with ahalogen atom, an optionally protected hydroxyl group or a C₁₋₆ alkoxygroup, and “optionally substituted amino group”, “optionally substitutedcarbon” or “optionally substituted nitrogen atom” mean an amino group, acarbon atom or a nitrogen atom, each of which may be substituted with ahalogen atom, an optionally protected hydroxyl group, a C₁₋₆ alkoxygroup or a C₁₋₆ alkyl group. Here, the protective group means an acetylgroup or the like.

[0411] In the general formula (I), when

[0412] is a quinuclidine having R⁸ and when c is 1, the cases where R⁸is a hydrogen atom or a hydroxyl group; Arl is an aromatic heterocycle;and W is one of (1) to (3), (6) to (11), and (16) to (19) are notincluded in the present invention.

[0413] In the present invention, the “C₁₋₆ alkyl chain” or “lower alkylgroup” has the same meaning as “C₁₋₆ alkyl group”, and means a linear orbranched C₁₋₆ alkyl group such as a methyl group, an ethyl group,an-propyl group, an i-propyl group, a sec-propyl group, a n-butyl group,an i-butyl group, a sec-butyl group, a t-butyl group, a n-pentyl group,an i-pentyl group, a sec-pentyl group, a t-pentyl group, a n-hexylgroup, an i-hexyl group, a 1,2-dimethylpropyl group, a 2-ethylpropylgroup, a 1-methyl-2-ethylpropyl group, a 1-ethyl-2-methylpropyl group, a1,1,2-trimethylpropyl group, a 1,1,2-trimethylpropyl group, a1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 2-ethylbutylgroup, a 1,3-dimethylbutyl group, a 2-methylpentyl group or a3-methylpentyl group. Further, the lower alkoxy group has the samemeaning as a C₁₋₆ alkoxy group and mens a C₁₋₆ alkyloxy group such as amethoxy group, an ethoxy group, a n-propoxy group, an i-propoxy group, asec-propoxy group, a n-butoxy group, an i-butoxy group, a sec-butoxygroup, a t-butoxy group, a n-pentoxy group, an i-pentoxy group, asec-pentoxy group, a t-pentoxy group, a n-hexoxy group, an i-hexoxygroup, a 1,2-dimethylpropoxy group, a 2-ethylpropoxy group, a1-methyl-2-ethylpropoxy group, a 1-ethyl-2-methylpropoxy group, a1,1,2-trimethylpropoxy group, 1,1,2-trimethylpropoxy group, a1,1-dimethylbutoxy group, a 2,2-dimethylbutoxy group, a 2-ethylbutoxygroup, a 1,3-dimethylbutoxy group, a 2-methylpentoxy group or a3-methylpentoxy group; a C₂₋₆ alkenyloxy group such as a vinyloxy group,an allyloxy group, an isopropoxyl group, a 1-propenyl-2-oxy group, a1-butenyl-1-oxy group, a 1-butenyl-2-oxy group, a 1-butenyl-3-oxy group,a 2-butenyl-1-oxy group or a 2-butenyl-2-oxy group; and a C₂₋₆alkynyloxy group such as an ethynyloxy group, a propynyloxy group, abutynyloxy group, a pentynyloxy group or a hexynyloxy group. Preferred“C₂₋₆ alkenyl group” is a linear or branched C₁₋₆ alkenyl groupincluding a vinyl group, an allyl group, an isopropenyl group, a1-propen-2-yl group, a 1-buten-1-yl group, a 1-buten-2-yl group, a1-buten-3-yl group, a 2-buten-1-yl group and a 2-buten-2-yl group.Examples of the “C₂₋₆ alkynyl group” include an ethynyl group, apropynyl group, a butynyl group, a pentynyl group and a hexynyl group.

[0414] The salts in the present invention means generallypharmacologically acceptable salts. Examples of these salts includehydrohalides such as hydrofluorides, hydrochlorides, hydrobromides andhydroiodides; inorganic acid salts such as sulfates, nitrates,perchlorates, phosphates, carbonates and bicarbonates; organiccarboxylates such as acetates, maleates, tartrates and fumarates;organic sulfonates such as methanesulfonates,trifluoromethanesulfonates, ethanesulfonates, benzene sulfonates andtoluene sulfonates; aminates such as alginates, aspartates andglutamates; salts with amines such as trimethylamine salts,triethylamine salts, procaine salts, pyridium salts andphenethylbenzylamine salts; alkali metal salts such as sodium salts andpotassium salts; and alkali earth metal salts such as magnesium saltsand calcium salts.

General Production Method

[0415] Various methods are considered as a method for producing thecompound represented by the formula (I) according to the presentinvention and the compound can be produced by a usual organic syntheticmethod. To state a typical method, for example, the following method maybe used to produce the compound.

[0416] The above production method is a method of producing the compound(γ) according to the invention of the patent application of this case bycoupling the aromatic heterocyclic compounds (α) and (β) with eachother. In the formula, X, Y and Z are the same as or different form eachother and each means (1) a carbon atom which may be substituted or (2) aheteroatom such as nitrogen atom, sulfur atom or oxygen atom, whereinthere is the case where Y further means a single bond. When Y means asingle bond, the ring to which X, Y and Z belong is a 5-membered ring.Here, in the case where X, Y and Z respectively represent the “carbonatom which may be substituted”, the term “may be substituted” means thatit may be substituted with the substituent shown in Arl in the formula(I) defined above. L means a leaving group and R means A in the generalformula (I) or its precursor. As for the precursor of A, when A has, forexample, an amino group, the precursor of A is a compound whose aminogroup is protected with an appropriate protective group (for example, atert-butoxycarbonyl group, a benzyl group, a benzyloxycarbonyl group, aborane complex, or the like). The protective group is deprotected in theprocess of the reaction or in the final step by a treatment with adeprotecting agent or the like (for example, trifluoroacetic acid,hydrochloric acid, hydrochloric acid-acetone, catalytic hydrogenationwith palladium carbon or the like, and so forth). The symbol drepresents the —(CH₂)_(n)—R¹ in the general formula (I) or itsprecursor. The symbol e represents the non-aromatic cyclic amino groupwhich may be substituted in the general formula (I) or its precursor.The leaving group L maybe any group generally so far as it is known as aleaving group useful in organic synthesis and is not particularlylimited. For example, halogen atoms such as a chlorine atom, a bromineatom or an iodine atom; substituted or unsubstituted acetoxy groups suchas an acetoxy group or a trifluoroacetoxy group; substituted sulfonyloxygroups such as a methanesulfonyloxy group, a trifluoromethanesulfonyloxygroup, a benzenesulfonyloxy group or a p-toluenesulfonyloxy group; andsubstituted phosphoryloxy groups such as a diphenoxyphosphoryloxy groupmay be proposed. Preferably, a halogen atom such as a chlorine atom, abromine atom or an iodine atom, a trifluoromethanesulfonyloxy group, orthe like may be proposed. As the palladium catalyst, for exampletetrakis(triphenylphosphine)palladium (0),bis(triphenylphosphine)palladium (II) chloride, or the like may be usedin an amount of 0.0001 to 0.1 molar equivalent. As the copper salt, forexample, cuprous iodide, cuprous chloride, or the like may be used in anamount of 0.0001 to 0.1 molar equivalent. As the base, for example,triethylamine, N,N-diisopropylethylamine, or the like may be used in anamount of 1 to5 equivalents. It is preferred that reaction be performedby using N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran,methanol, or a mixed solvent thereof as a solvent at a reactiontemperature of 0° C. to 140° C.

[0417] Subjecting the compound (γ) described above to reduction with ametal hydride complex compound such as lithium aluminum hydride orcatalytic hydrogenation with a catalyst such as platinum oxide (IV) orpalladium activated carbon can convert the triple bond of the compound yto a double bond or can derive the compound y to a saturatedhydrocarbon. Also, hydration reaction by allowing mercury oxide (II) toact under acidic conditions or the like can derive the compound γ with atriple bond to a carbonyl compound.

[0418] By the production method described above, the compound (ε) of thepresent invention can be produced. In the reaction scheme, X, Y, Z, d, eand L have the same meanings as defined above. L is, for example, achlorine atom, a bromine atom, an iodine atom, or atrifluoromethanesulfonyloxy group. M means a metal atom which may besubstituted, and preferred examples of M include tributyltin anddihydroxyboron. As the palladium catalyst,tetrakis(triphenylphosphine)palladium (0),bis(triphenylphosphine)palladium (II) chloride or the like can be usedin an amount of 0.0001 to 0.1 molar equivalent. The solvent includestoluene, xylene, N,N-dimethylformamide and N-methylpyrrolidone. Reactiontemperatures of from room temperature to 150° C. are used. When themetal M is boron, an inorganic base such as sodium carbonate or anorganic base such as triethylamine is used as the base and an organicsolvent containing water is also used as the solvent.

[0419] The production method described above is a method in which anorganolithium compound and then a ketone derivative (η) is allowed toact on the aromatic compound (α) to produce compounds (θ) and (ι) of thepresent invention. In the reaction scheme, X, Y, Z, d and e have thesame meanings as defined above. L means a halogen atom. R′ and R″represent elements that constitute A in the general formula (I). Theorganolithium compound may be used in an amount of 1 to 20 equivalents.Used as the solvent are diethyl ether, tetrahydrofuran, dimethoxyethane,dioxane, hexane, benzene, etc. and mixed solvents thereof. The reactiontemperature used is from −100° C. to room temperature. Allowing theketone derivative (η) to act using the same solvent and reactiontemperature as those for an organometal-halogen exchange reaction canproduce the compound (θ). Also, subsequently performing an acidtreatment or a dehydration reaction with a halogenating reagent, asulfonating reagent, an esterifying reagent, a dehydrating reagent, orthe like can produce the compound (ι).

[0420] Allowing carbon dioxide to act on the compound (α) after theorganometal-halogen exchange reaction can synthesize an aromaticcarboxylic acid, and allowing an amine derivative to the aromaticcarboxylic acid by a conventional method can synthesize an acid amidecompound. Also, the Curtius rearrangement reaction or the like canderive the obtained aromatic carboxylic acid to an aromatic aminederivative and allowing a carboxylic acid derivative to act by aconventional method can also synthesize an acid amide compound.

[0421] The production method described above is a method in which acompound (κ) is allowed to act on the aromatic compound (α) to produce acompound (λ) of the present invention. In the reaction scheme, X, Y, Z,e and d have the same meanings as defined above. L means a halogen atom.R¹, R′ and R″ represent elements that constitute W and A in the generalformula (I). The compound (κ) can be derived from a carboxylic acidester synthesized by a conventional method of the Wittig-Horner-Emmonsreaction. The compound (λ) can be produced by allowing the compounds (α)and (κ) to act in the presence of a metal hydride such as sodiumhydride, sodium alkoxide, lithium hydroxide, sodium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, or an organolithium compound under room temperature to heatedconditions.

[0422] Next, the production method of the intermediate (α) that isinvolved in the production of the compounds of the present invention,divided into (α-A), (α-B), (α-C), (α-D) and (α-E), will be describedhereinbelow.

[0423] The production method described above is a method in which theintermediate (α-A) that is involved in the production of the compoundsof the present invention is produced. In the formulae described above,R^(A) represents a hydrogen atom, a lower alkyl group, a lower alkoxygroup or a halogen atom; L represents a leaving group, for example, ahalogen atom and the like; Ar represents an aromatic ring which may besubstituted; and CyA represents a cyclic amino group which may besubstituted or a cyclic amido group which may be substituted. Reactingan isonicotinic acid derivative (A-1) with 1 to 100 equivalents of ahalogenating agent (for example, oxalyl chloride, thionyl chloride, orthe like) in a solvent (for example, methylene chloride, chloroform,benzene, toluene, or the like) at 0° C. to 140° C. can provide (A-2).Subsequently, performing the Friedel-Crafts reaction using an excessamount of an aromatic hydrocarbon, for example, benzene, toluene,anisole, fluorobenzene, or the like at −50° C. to 140° C. with additionof a Lewis acid (for example, anhydrous aluminum chloride) can produce(A-3). Reacting (A-3) with 1 to 10 equivalents of a cyclic amine whichmay be substituted in the absence of a solvent or in the presence of 1to 10 equivalents of a base (for example,1,8-diazabicyclo[5.4.0]-7-undecene or the like) in a solvent, forexample, 1-methylpyrrolidinone or the like at room temperature to 200°C. can synthesize (A-4). Also, reacting 0.1 to 10 equivalents of acopper compound (for example, copper powder, copper iodide, or the like)or the like with 1 to 10 equivalents of a base (for example, potassiumcarbonate or the like) and 1 to 10 equivalents of a cyclic amide whichmay be substituted in a solvent such as 1-methylpyrrolidinone cansynthesize (A-4). Then, performing the Clemmensen reduction with usingzinc amalgam prepared from 1 to 10 times amount of zinc white, 0.1 to 1time amount of mercury chloride (II), 0.1 to 1 time amount ofconcentrated hydrochloric acid and 1 to 10 times amount of water, and 0to 10 times amount of water, 1 to 100 times amount of concentratedhydrochloric acid, and 0 to 10 times amount of a solvent, for example,toluene, ethanol, dioxane, acetic acid or the like, at 0° C. to 140° C.can synthesize (A-5). Alternatively, the reduction reaction can beperformed by adding 1 to 10 equivalents of hydrazine, 1 to 10equivalents of a base (for example, sodium hydroxide, potassiumhydroxide, sodium alkoxide, potassium tert-butoxide, or the like) to(A-4) in the absence of a solvent or in a solvent, for example, ethanol,ethylene glycol, diethylene glycol, triethylene glycol, or the like atroom temperature to 250° C. Also, (A-5) can be synthesized by reducingthe ketone into a hydroxyl group with 1 to20 equivalents of a metalhydride (for example, lithium aluminum hydride, sodium borohydride, orthe like) in a solvent, for example, ether, tetrahydrofuran, methanol,ethanol, or the like; acetylating the hydroxyl group as it is was or byaddition of, for example 1 to 10 times amount of acetic anhydride and anexcess amount of pyridine or halogenating the hydroxyl group with ahalogenating agent (for example, oxalyl chloride, thionyl chloride,phosphorus oxychloride, or the like); and subsequent catalytichydrogenation reaction with 0.1 to 1 equivalent of a catalyst (palladiumcarbon, palladium hydroxide-carbon, or the like) under hydrogen streamat atmospheric pressure to 100 atm in the absence of a solvent or in asolvent, for example, methanol, ethanol, ethyl acetate, tetrahydrofuran,toluene, or the like. Then, reacting (A-5) with 1 to 10 equivalents ofN-bromosuccinimide, N-iodosuccinimide, or the like in a solvent (forexample, N,N-dimethylformamide, N-methylpyrrolidinone or the like) at 0°C. to 100° C. can synthesize (α-A). Also, reacting (A-5) with 1 to 10equivalents of bromine or iodine in a basic aqueous solution (forexample, an aqueous sodium hydrogen carbonate solution, an aqueouspotassium carbonate solution, or the like) at 0° C. to 100° C. cansynthesize (α-A), or reacting (A-5) with 1 to 10 equivalents of bromineor iodine monochloride in acetic acid at 0° C. to 150° C. can synthesize(α-A).

[0424] Alternatively, (A-5) can be synthesized from (A-3) by thefollowing production method. Allowing 1 to 100 equivalents of sodiummethoxide to act on (A-3) in methanol at room temperature to 150° C. cansynthesize (A-6), and then (A-7) can be synthesized therefrom in thesame manner as the reaction of from (A-4) to (A-5). Then, heating (A-7)under reflux at 50 to 150° C. in an excess amount of hydrobromic acidcan demethylate it and reacting the resultant with 1 to 10 equivalentsof a sulfonylating agent (for example, methanesulfonyl chloride,toluenesulfonyl chloride, anhydrous trifluoromethanesulfonyl,N-phenyltrifluoromethanesulfonimide, or the like) in the presence of 1to 10 equivalents of a base (for example, pyridine, triethylamine,4-dimethylaminopyridine, or the like) in a solvent, for example,methylene chloride, tetrahydrofuran, ethyl acetate, toluene or the likeat 0° C. to 100° C. can synthesize (A-8). Then, (A-5) can also besynthesized by reacting (A-8) with 1 to 10 equivalents of a cyclic aminewhich may be substituted in the absence of a solvent or in the presenceof 1 to 10 equivalents of abase (for example,1,8-diazabicyclo[5.4.0]-7-undecene) in a solvent, for example,1-methylpyrrolidinone or the like at room temperature to 200° C.

[0425] Further, reacting (A-7) 1 to 10 equivalents of bromine or iodinein the absence of a solvent, or in a solvent, for example methanol,ethylene glycol, or the like in the presence of a base (for example, anaqueous sodium hydrogen carbonate solution, an aqueous potassiumcarbonate solution, or the like) at 0° C. to 100° C. can synthesize(A-9) Then, heating (A-9) under reflux at 50 to 150° C. in an excessamount of hydrobromic acid can demethylate it and reacting the resultantwith 1 to 10 equivalents of a sulfonylating agent (for example,methanesulfonyl chloride, toluenesulfonyl chloride, anhydroustrifluoromethanesulfonyl, N-phenyltrifluoromethanesulfonimide or thelike) in the presence of 1 to 10 equivalents of abase (for example,pyridine, triethylamine, 4-dimethylaminopyridine, or the like) in asolvent, for example, methylene chloride, tetrahydrofuran, ethylacetate, toluene or the like at 0° C. to 100° C. can synthesize (A-10).Then, (α-A) can also be synthesized by reacting (A-10) with 1 to 10equivalents of a cyclic amine which may be substituted in the absence ofa solvent or in the presence of 1 to 10 equivalents of abase (forexample, 1,8-diazabicyclo[5.4.0]-7-undecene) in a solvent, for example,1-methylpyrrolidinone, or the like at room temperature to 200° C.

[0426] The production method described above is a method in which theintermediate (α-B) that is involved in the production of the compoundsof the present invention is produced. In the formulae described above, Lrepresents a leaving group, for example, a halogen atom, or the like;R^(B) represents a hydrogen atom, a lower alkyl group, a lower alkoxygroup or a halogen atom; Ar represents an aromatic ring which may besubstituted; and CyA represents a cyclic amino group which may besubstituted or a cyclic amido group which may be substituted. Byreacting a nicotinic acid derivative (B-1) with 1 to 100 equivalents ofa halogenating agent (for example, oxalyl chloride, thionyl chloride, orthe like) in a solvent (for example, methylene chloride, chloroform,benzene, toluene, or the like) at 0° C. to 140° C., (B-2) can beobtained. Subsequent addition of a Lewis acid (for example, anhydrousaluminum chloride) and performing the Friedel-Crafts reaction using anexcess amount of an aromatic hydrocarbon, for example, benzene, toluene,anisole, fluorobenzene, or the like at −50° C. to 140° C. can produce(B-3) Allowing 1 to 100 equivalents of sodium methoxide to act on (B-3)at room temperature to 150° C. can synthesize (B-4). Then, performingthe Clemmensen reduction with using zinc amalgam prepared from 1 to 10times amount of zinc white, 0.1 to 1 time amount of mercury chloride(II), 0.1 to 1 time amount of concentrated hydrochloric acid, and 1 to10 times amount of water, and 0 to 10 times amount of water, 1 to 100times amount of concentrated hydrochloric acid, and 0 to 10 times amountof a solvent, for example, toluene, ethanol, dioxane, acetic acid, orthe like, at 0° C. to 140° C. can synthesize (B-5). Alternatively, areduction reaction of (B-4) can be performed by adding 1 to 10equivalents of hydrazine, 1 to 10 equivalents of a base (for example,sodium hydroxide, potassium hydroxide, sodium alkoxide, potassiumtert-butoxide, or the like) to (B-4) in the absence of solvents or in asolvent, for example, ethanol, ethylene glycol, diethylene glycol,triethylene glycol, or the like at room temperature to 250° C. tosynthesize (B-5). Also, (B-4) can be reduced by reducing the ketone intoa hydroxyl group with 1 to 20 equivalents of a metal hydride (forexample, lithium aluminum hydride, sodium borohydride, or the like) in asolvent, for example, ether, tetrahydrofuran, methanol, ethanol, or thelike; acetylating the hydroxyl group as it is or by addition of, forexample 1 to 10 times amount of acetic acid anhydride and an excessamount of pyridine or halogenating the hydroxyl group with ahalogenating agent (for example, oxalyl chloride, thionyl chloride,phosphorus oxychloride or the like); and subsequent catalytichydrogenation reaction with 0.1 to 1 equivalent of a catalyst(palladium-carbon, palladium hydroxide-carbon, or the like) underhydrogen stream at atmospheric pressure to 100 atm in the absence ofsolvents or in a solvent, for example, methanol, ethanol, ethyl acetate,tetrahydrofuran, toluene or the like. Then, reacting (B-5) with, forexample, 1 to 10 equivalents of bromine or iodine in the absence ofsolvents or in a solvent, for example, methanol, ethylene glycol or thelike in the presence of a base (for example, an aqueous sodium hydrogencarbonate solution, an aqueous potassium carbonate solution, or thelike) at 0° C. to 100° C. can synthesize (B-6). Then, reacting (B-6)with 1 to 10 equivalents of a cyclic amine which may be substituted inthe presence of 0.001 to 1 equivalent of 0-valent to divalent palladium(palladium acetate, tris(dibenzylideneacetone)dipalladium, or the like)and 0.001 to 1 equivalent of phosphorus ligand (tri-o-tolylphosphine,tri-tert-butylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, orthe like), 1 to 10 equivalents of abase (for example, potassiumtert-butoxide, potassium phosphate, cesium carbonate, or the like) in asolvent such as toluene or dioxane at 0° C. to 200° C. can synthesize(B-7). (B-7) can also be synthesized by allowing 1 to 10 equivalents ofa cyclic amide which maybe substituted and I to 10 equivalents of a base(for example, potassium carbonate, or the like) to act on (B-6) withusing 0.1 to 10 equivalents of a copper compound (for example, copperpowder, copper iodide, or the like), or the like in a solvent such as1-methylpyrrolidinone. Then, heating (B-7) under reflux at 50 to 150° C.in an excess amount of hydrobromic acid can demethylate it and reactingthe resultant with 1 to 10 equivalents of a sulfonylating agent (forexample, methanesulfonyl chloride, toluenesulfonyl chloride, anhydroustrifluoromethanesulfonyl, N-phenyltrifluoromethanesulfonimide, or thelike) in the presence of 1 to 10 equivalents of abase (for example,pyridine, triethylamine, 4-dimethylaminopyridine or the like) in asolvent, for example, methylene chloride, tetrahydrofuran, ethylacetate, toluene or the like at 0° C. to 100° C. can synthesize (α-B).Also, (α-B) can be synthesized by heating the demethylated product underreflux with a halogenating agent (for example, phosphorus oxychloride,phosphorus pentoxide, thionyl chloride, phosphorus oxybromide, or thelike) in the absence of solvents or in a solvent such as a halogensolvent (for example, chloroform, dichloroethane, or the like), anaromatic solvent (for example, benzene, toluene, chlorobenzene, or thelike), or N,N-dimethylformamide at 50° C. to 150° C.

[0427] The production method described above is a method in which theintermediate (α-C) that is involved in the production of the compoundsof the present invention is produced. In the formulae described above,R¹ and n are the same as those in the general formula (I) ; L representsa leaving group, for example, a halogen atom or the like; R^(C)represents a hydrogen atom, a lower alkyl group, a lower alkoxy group ora halogen atom; and CyA represents a cyclic amino group which may besubstituted or a cyclic amido group which may be substituted. Allowing 1to 100 equivalents of sodium methoxide to act on a pyridine derivative(C-1) in methanol at room temperature to 150° C. can synthesize (C-2).By reacting (C-2) with a commercially available Grignard reagent or theGrignard reagent obtained by using a solvent such as ether ortetrahydrofuran and reacting R¹(CH₂)_(n)X with an equivalent ofmagnesium at 0° C. to 100° C. in the presence of 0.001 to 1 equivalentof a nickel compound (for example,(1,3-bis(triphenylphosphino)propane)nickel (0) chloride, or the like) ina solvent such as ether or tetrahydrofuran at −50° C. to 100° C., (C-3)can be obtained. Then, (C-3) can be treated in an excess amount ofhydrobromic acid at 50° C. to 150° C. to demethylate it. Reacting theresultant with 1 to 10 equivalents of a sulfonylating agent (forexample, methanesulfonyl chloride, toluenesulfonyl chloride, anhydroustrifluoromethanesulfonyl, N-phenyltrifluoromethanesulfonimide, or thelike) in the presence of 1 to 10 equivalents of abase (for example,pyridine, triethylamine, 4-dimethylaminopyridine, or the like) in asolvent, for example, methylene chloride, tetrahydrofuran, ethylacetate, toluene, or the like at 0° C. to 100° C. can synthesize (C-4).Reacting (C-4) with 1 to 10 equivalents of a cyclic amine which may besubstituted in the absence of solvents or in the presence of 1 to 10equivalents of a base (for example, 1,8-diazabicyclo[5.4.0]-undecene orthe like) in a solvent, for example, 1-methylpyrrolidinone or the likeat room temperature to 200° C. can synthesize (C-5). Also, allowing 1 to10 equivalents of a base (for example, potassium carbonate or the like)and 1 to 10 equivalents of a cyclic amide which may be substituted toact on (C-4) with using 0.1 to 10 equivalents of a copper compound (forexample, copper powder, copper iodide, or the like) in a solvent such as1-methylpyrrolidinone can also synthesize (C-5). Reacting (C-5) with 1to 10 equivalents of N-bromosuccinimide, N-iodosuccinimide or the likein a solvent (for example, N,N-dimethylformamide, N-methylpyrrolidinone,or the like) at 0° C. to 100° C. can synthesize (α-C). Also, reacting(C-5) with 1 to 10 equivalents of bromine or iodine in a basic aqueoussolution (for example, an aqueous sodium hydrogen carbonate solution, anaqueous potassium carbonate solution, or the like) at 0° C. to 100° C.can synthesize (α-C), or reacting (C-5) with 1 to 10 equivalents ofbromine or iodine monochloride in acetic acid at 0° C. to 150° C. cansynthesize (α-C).

[0428] The production method described above is a method in which theintermediate (α-D) that is involved in the production of the compoundsof the present invention is produced. In the formulae described above,R¹ and n are the same as those in the general formula (I); L representsa leaving group, for example, a halogen atom or the like; and CyArepresents a cyclic amino group which may be substituted or a cyclicamido group which maybe substituted. Allowing 1 to 10 equivalents ofR¹(CH₂)_(n)COCl to act on Meldrum's acid (D-1)in the presence of a basesuch as pyridine in a solvent such as dichloromethane at −50° C. to 100°C. and then allowing an excess amount of tert-butanol to act thereon at50° C. to 150° C, and subsequently allowing N,N-dimethylformamidedimethyl acetal to act thereon in a solvent such as toluene at −50° C.to 100° C. can synthesize (D-2). Allowing 1 to 100 equivalents oftrifluoroacetic acid to act on (D-2) in a solvent such asdichloromethane at −50° C. to 100° C., then allowing 1 to 10 equivalentsof quanidine to act thereon in the presence of 1 to 10 equivalents of abase (for example, sodium ethoxide or the like) in an ethanol solvent orthe like at 50° C. to 150° C. can synthesize (D-3). Allowing 1 to 10equivalents of a halogenating agent (for example, bromine,N-bromosuccinic acid or the like) to act on (D-3) in the presence of 0to 10 equivalents of a base (for example, sodium hydrogen carbonate orthe like) in a solvent such as N,N-dimethylformamide or methanol at −50°C. to 100° C. can give rise to (D-4). Reacting (D-4) with 1 to 10equivalents of a diazotizing agent such as isoamyl nitrite, an excessamount of a halogen solvent (for example, diiodomethane or the like), ahalogenating agent (for example, cuprous iodide, cupric chloride, or thelike), and a solvent such as tetrahydrofuran at 0° C. to 100° C. tohalogenate the amino group, and then reacting the resultant with 1 to 10equivalents of a cyclic amine which may be substituted in the absence ofsolvents or in the presence of 1 to 10 equivalents of a base (forexample, 1,8-diazabicyclo[5.4.0]-undecene or the like) in a solvent, forexample, 1-methylpyrrolidinone or the like at room temperature to 200°C. can synthesize (α-D). Also, allowing 1 to 10 equivalents of a base(for example, potassium carbonate or the like) and 1 to 10 equivalentsof a cyclic amide which may be substituted to act on (D-4) with using0.1 to 10 equivalents of a copper compound (for example, copper powder,copper iodide or the like) in a solvent such as 1-methylpyrrolidinonecan also synthesize (α-D).

[0429] The production method described above is a method in which theintermediate (α-E) that is involved in the production of the compoundsof the present invention is produced. In the formulae described above,R¹, n, X, Y, and Z are the same as those in the general formula (I); Lrepresents a leaving group, for example, a halogen atom or the like; andCyA represents a cyclic amino group which may be substituted or a cyclicamido group which may be substituted. Allowing 1 to 10 equivalents ofchloromethyl methyl ether to act on (E-1) in the presence of a base(forexample, sodium hydride, potassium hydroxide, cesium carbonate, or thelike) in a solvent (for example, tetrahydrofuran, diethyl ether,dioxane, or the like) to methoxymethylate it, and then allowing 1 to 10equivalents of Grignard reagent (for example benzylmagnesium bromide orthe like) to act on the resultant in the presence of 0.001 to 1equivalent of a nickel compound (for example,1,3-bis(diphenylphosphino)propane nickel (0) chloride or the like) in asolvent such as diethyl ether or tetrahydrofuran at −50° C. to 100° C.can synthesize (E-2). Allowing 1 to 100 equivalents of an acid (forexample, trifluoroacetic acid or the like) to act on (E-2), thenallowing a halogenating agent (for example, sodium iodide and sodiumhypochlorite, N-bromosuccinimide or the like) and 0 to 10 equivalents ofa base (for example, sodium hydroxide or the like) to act on theresultant in a solvent such as methanol or ethanol, and subsequentlyallowing 1 to 10 equivalents of chloromethyl methyl ether to act thereonin the presence of 1 to 10 equivalents of abase (for example, sodiumhydride, potassium hydroxide, cesium carbonate or the like) in a solvent(for example, tetrahydrofuran, diethyl ether, dioxane or the like) cansynthesize (E-3). Performing reaction of (E-3) in the presence of 0.001to 1 equivalent of 0-valent to divalent palladium (palladium acetate,tris(dibenzylideneacetone)dipalladium or the like) and 0.001 to 1equivalent of phosphorus ligand (tri-o-tolylphosphine,tri-tert-butylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl orthe like), and 1 to 10 equivalents of a base (for example, potassiumtert-butoxide, potassium phosphate, cesium carbonate or the like) in asolvent such as toluene or dioxane at 0° C. to 200° C. can produce(E-4). (E-4) can also be synthesized by allowing 1 to 10 equivalents ofa cyclic amide which may be substituted and 1 to10 equivalents of a base(for example, potassium carbonate or the like) to act on (E-3) withusing 0.1 to 10 equivalents of a copper compound (for example, copperpowder, copper iodide or the like) or the like in a solvent such as1-methylpyrrolidinone. Then, treating (E-4) with an excess amount of anacid (for example, trifluoroacetic acid) to deprotect methoxymethylgroup and reacting the resultant with 1 to 10 equivalents of asulfonylating agent (for example, methanesulfonyl chloride,toluenesulfonyl chloride, anhydrous trifluoromethanesulfonyl,N-phenyltrifluoromethanesulfonimide or the like) in the presence of 1 to10 equivalents of abase (for example, pyridine, triethylamine,4-dimethylaminopyridine or the like) in a solvent, for example,methylene chloride, tetrahydrofuran, ethyl acetate, toluene or the likeat 0° C. to 100° C. can synthesize (α-E). Also, (α-E) can be produced byheating the deprotected product under reflux with a halogenating agent(for example, phosphorus oxychloride, phosphorus pentoxide, thionylchloride, phosphorus oxybromide or the like) in the absence of solventsor in a solvent such as a halogen solvent (for example, chloroform,dichloroethane or the like), an aromatic solvent (for example, benzene,toluene, chlorobenzene or the like), or N,N-dimethylformamide at 50° C.to 150° C.

[0430] Next, the production method for the intermediate (6) that isinvolved in the production of the compounds of the present inventionwill be described hereinbelow.

M-Ar—R (δ)

[0431] Note that the primary or secondary amino group contained in theintermediate (δ) maybe protected with a stable protective group (forexample, a tert-butoxycarbonyl group, a benzyl group, abenzyloxycarbonyl group or the like) during the production process, orthe tertiary amino group contained in the intermediate (δ) may beprotected as a borane complex. Further, in case where the protectivegroup is deprotected in the production process, there maybe a case wherea protective group is introduced again.

[0432] By the production method described above, the compound (b) of thepresent invention can be produced. Ar, R, R′, and R″ represent elementsthat constitute W and A in the general formula (I). Further, Mrepresents a substituent having a metal and L′ represents a halogenatom. In (δ-1), M represents, for example, tributyltin, boric acidesterified with N-methyldiethanolamine, or the like. (δ) can besynthesized by allowing 1 to 10 equivalents, preferably 1 to 3equivalents of an organolithium reagent (for example, n-butyllithium,sec-butyllithium, tert-butyllithium or the like) to act on (δ-1) at−100° C. to 0° C. in a solvent (for example, diethyl ether,tetrahydrofuran, or the like) and subsequently allowing (η) to act onthe resultant at −100° C. to room temperature.

[0433] Then, the production method for the intermediate (κ) that isinvolved in the production of the compound of the present invention willbe described hereinbelow.

[0434] Note that the primary or secondary amino group contained in theintermediate (κ) maybe protected with a stable protective group (forexample, a tert-butoxycarbonyl group, a benzyl group, abenzyloxycarbonyl group or the like) during the production process, orthe tertiary amino group may be protected as a borane complex. Further,in case the protective group is deprotected in the production process,there maybe a case where a protective group is introduced again.Further, the intermediate (κ) can also be synthesized by the methoddescribed in WO 96/26938.

[0435] By the production method described above, the compound (κ) of thepresent invention can be produced. R¹, R′, and R″ represent elementsthat constitute W and A in the general formula (I). Reacting (η) with 1to 10 equivalents, preferably 1 to 3 equivalents of Wittig-Horner-Emmonsreagent (κ-1) in a solvent (for example, methanol, ethanol,tetrahydrofuran, dioxane, diethyl ether, toluene, benzene or the like)in the presence of 1 to 2 equivalents of a base (for example, sodiumhydride, sodium methoxide, sodium hydroxide, n-butyllithium or the like)with respect to (κ-1) at −50° C. to 100° C. can synthesize (κ-2). Thereare geometric isomers of (κ-2). The isomers can be isolated bysubjecting (κ-2) or (κ-3) to silica gel column chromatography or thelike. (κ-2) can be converted to (κ-3) by performing a reduction reactionof (κ-2) in a solvent (for example, tetrahydrofuran, diethyl ether,toluene or the like) in the presence of a stoichiometric amount of or anexcess amount of a reducing agent (for example, diisobutylaluminumhydride, lithium aluminum hydride, or the like) at −100° C. to 50° C.Subsequently, (κ-3) can be converted into (κ) by allowing 1 to 10equivalents of a sulfonylating agent (for example, methanesulfonylchloride, toluenesulfonyl chloride or the like) to act on (κ-3) in asolvent (for example, dichloromethane, N,N-dimethylformamide,tetrahydrofuran or the like) in the presence of 1 to 10 equivalents ofabase (for example, pyridine, triethylamine or the like) at 0° C. to 50°C. Further, 1 to 10 equivalents of lithium chloride may be added to thereaction mixture. Also, (κ) can be synthesized by allowing 1 to 10equivalents of a halogenating agent (for example, phosphorus tribromide,phosphorus trichloride or the like) and 0 to 10 equivalents of a base(for example, pyridine, quinoline or the like) to act on (κ-3); allowing1 to 10 equivalents of triphenyl phosphonate and 1 to 10 equivalents ofan alkyl halide (for example, benzyl chloride or the like) to act on(κ-3); or allowing 1 to 10 equivalents of triphenylphosphine and anexcess amount of carbon tetrahalide (for example, carbon tetrachloride)to act on (κ-3) in a solvent (for example, dichloromethane,N,N-dimethylformamide, tetrahydrofuran, toluene or the like) Next, theproduction method of the intermediate (β) that is involved in theproduction of the compounds of the present invention, divided into(β-A), (β-B) and (β-C), will be described hereinbelow.

[0436] Note that the primary or secondary amino group contained in theintermediate (β) may be protected with a stable protective group (forexample, a tert-butoxycarbonyl group, a benzyl group, abenzyloxycarbonyl group or the like) during the production process, orthe tertiary amino group contained in the intermediate (β) maybeprotected as a borane complex. Further, in case where the protectivegroup is deprotected in the production process, there maybe a case wherea protective group is introduced again.

[0437] By the production method described above, the compound (β-A) ofthe present invention can be produced. In the reaction scheme, R′ and R″represent elements that constitute A in the general formula (I).Dissolving 1 to 10 equivalents, preferably 1 to 3 equivalents based on(η) of trimethylsilylacetylene in a solvent (for example, hexane,benzene, toluene, tetrahydrofuran, diethyl ether, or the like), allowing0.1 to 10 equivalents, preferably 0.5 to 2 equivalents based ontrimethylsilylacetylene of an organolithium reagent (for example,n-butyllithium or the like) to act on the trimethylsilylacetylene at−100° C. to room temperature, preferably −80° C. to 0° C., andsubsequently allowing a ketone derivative (η) to act on the resultant,followed by performing hydrolysis with 1 to 10 equivalents of a base(potassium carbonate, sodium hydroxide, or the like) in the absence of asolvent or in the presence of a solvent (methanol, ethanol,dimethylformamide, tetrahydrofuran, water, or the like) can synthesize(β-A).

[0438] By the production method described above, the compound (β-B) ofthe present invention can be produced. In the reaction scheme, L means aleaving group, and R′, R″, R′″ and R″″ represent elements thatconstitute A in the general formula (I). Adding a solvent (for example,benzene, toluene, chloroform, dichloromethane, or the like) to (β-A),adding 1 to 100 equivalents of an acid anhydride or a acid halogencompound (for example, acetic anhydride or the like) at −50° C. to 100°C., preferably −20° C. to room temperature, and then adding 0.01 to 10equivalents of a Lewis acid (for example, trimethylsilyl triflate) cansynthesize (B′-1). Adding a solvent (for example, benzene, toluene,tetrahydrofuran, chloroform, dichloromethane, or the like) to (B′-1) andallowing 1 to 100 equivalents of an amine derivative (B′-2) and 0.01 to10 equivalents of a copper compound (for example, cuprous chloride orthe like) to act on (B′-1) can produce (β-B).

[0439] By the production method described above, the compound (β-C) ofthe present invention can be produced. In the reaction scheme, Lrepresents a leaving group (for example, a halogen atom or the like) andA represents elements that constitutes the general formula (I).Dissolving (C′-1) in a solvent (for example, N,N-dimethylformamide,tetrahydrofuran or the like), reacting the resultant with 0.5 to 10equivalents of an alkali metal reagent (for example, sodium, sodiumhydride, potassium hydride or the like) at −50° C. to room temperatureand subsequently adding 1 to 10 equivalents of (C′-2) at −100° C. toroom temperature, followed by elevating the reaction temperature fromroom temperature to 100° C., whereby can synthesize (β-C).

[0440] No particular limitation is imposed on the dosage form of thecompound according to the present invention and either oraladministration or parenteral administration according to a method whichis usually used is acceptable. The compound may be made intopreparations of a tablet, powder, granule, capsule agent, syrup agent,troche, inhalant, suppository, injection, ointment, ophthalmic ointment,ophthalmic solution, collunarium, ear drop, cataplasm and lotion, andadministered. In the preparation of these forms, fillers, binders,lubricants, colorants, flavoring agents, and if necessary, stabilizers,emulsifiers, absorbefacient agents, surfactants, pH regulators,antiseptics and antioxidants etc. may be used and components which areusually used as raw materials of medicinal preparations are formulatedto prepare a medicine by a usual method. Examples of these componentsinclude animal or vegetable oils such as soybean oil, beef tallow andsynthetic glyceride; hydrocarbons such as liquid paraffin, squalane andsolid paraffin; ester oils such as octyldodecyl myristate and isopropylmyristate; higher alcohols such as cetostearyl alcohol and behenylalcohol; silicon resins; silicon oils; surfactants such aspolyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerolfatty acid ester, polyoxyethylenesorbitan fatty acid ester,polyoxyethylene hydrogenated castor oil andpolyoxyethylene/polyoxypropylene block copolymers; water-solublepolymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinylpolymers, polyethylene glycol, polyvinylpyrrolidone and methylcellulose; lower alcohols such as ethanol and isopropanol;polyhydricalcohols such as glycerol, propylene glycol, dipropylene glycol andsorbitol; sugars such as glucose and cane sugar; inorganic powders suchas silicic acid anhydride, aluminum magnesium silicate and aluminumsilicate; and purified water.

[0441] The medicine according to the present invention is administeredto an adult patient at a dose of generally about 30 μg to 10 g,preferably 100 μg to 5 g and more preferably 100 μg to 100 mg in thecase of oral administration and about 30 μg to 1 g, preferably 100 μg to500 mg and more preferably 100 μg to 30 mg in the case of injection inone to several parts a day although the dose differs depending on thedegree of a symptom, age, sex, weight, dosage form and type of disease.

[0442] The biochemical activities of the compound according to thepresent invention and the effects (squalene synthase activity andcholesterol biosynthesis inhibitive activity) of the compound as amedicine may be evaluated by the following methods.

Test Example 1 Measurement of Squalene Synthase Inhibitive Activity byUsing a Rat Liver Microsome

[0443] (I) The reaction was run on a scale of 500 μl. 200 μl of asolution containing 125 mM tris-hydrochloric acid (pH: 7.3), 2.5 mMmagnesium chloride, 5 mM potassium fluoride and 10 mM reduction typenicotinamidoadenine dinucleotide phosphoric acid, 100 μl of the specimensolution with a 5-fold concentration, 100 μl of distilled water and 50μl of 0.4 to 1 mg/ml rat liver microsome prepared by the followingmethod were mixed.

[0444] (II) The above mixture was pre-incubated at 37° C. for 10 minutesand thereafter, 50 μl of 100 μM [³H)-farnesylpyrophosphoric acid (30mCi/mmol, NEN) was added to the mixture to start a reaction. Thereaction was continued at 37° C. for 10 minutes. 1 ml of ethanol wasadded to the resulting mixture to terminate the reaction and then 1 mlof distilled water and 3 ml of petroleum ether were added to thereaction solution, which was then shaken for 30 minutes. The water phasewas separated from the organic phase, the water phase was frozen at −70°C. in dry ice/methanol and the radio activity of the organic phase wasmeasured using a liquid scintillator. Or the organic phase wasevaporated to dryness using nitrogen gas and the residue was dissolvedas a marker in 25 μl of chloroform containing squalene, farnesol andcholesterol. This sample was spotted on a TCL plate (Merck) anddeveloped using heptane for 15 to 20 minutes. A band of squalene was cutfrom the plate to measure the radio activity by using a liquidscintillation counter. The data was expressed by a concentration (IC₅₀)at which 50% of the radio activity of a control group was inhibited.

Preparation Method for Rat Liver Microsome

[0445] All the following operations were performed on ice andcentrifugation was performed at 4° C. Liver was extracted from a maleSpraugue-Dawly rat (hereinafter referred to as “SD rat”) (8 to 9 weeksin age) and perfused with 1.15% potassium chloride to remove the blood.Then, the liver was finely excised with a pair of scissors andhomogenized by use of a Teflon homogenizer. The obtained sample wascentrifuged at 16,000× g for 15 minutes twice. The supernatant wasfurther centrifuged at 105,000× g for 60 minutes and the obtainedresidue was used as a microsome fraction, which was suspended in 25 mMTris-hydrochloric acid solution. The protein concentration of thesuspension was quantitated by the Bradford method and the suspension wasadjusted to 20 mg/ml with the same solution and stored at −70° C.

Test Example 2 Measurement of Cholesterol Biosynthesis InhibitiveActivity in a Rat Liver Cell

[0446] A liver cell was isolated from a male SD rat according to a usualmethod (collagenase perfusion method) and subjected to an experiment.

[0447] The isolated liver cells were planted in an amount of 500 μlevery well on a Type collagen coated 24 well plate (cell density: 4×10⁵cell/ml). As the cell culture solution, a Williams' E medium (adjustedto pH 7.4) containing 10% FCS, 1 μM insulin, 1 μM dexamethasone, 100units/ml penicillin and 100 μg/ml streptomycin was used. After the livercells were incubated in a CO₂ incubator for 2 hours, unattached cellswere removed and the liver cells were further incubated overnight.

[0448] After the culture medium was exchanged, the specimen diluted in a10% DMSO-90% cell culture solution was added to each well inan amount of5 μl. DMSO (final concentration: 0.1%) was added toacontrolgroup. A[1-¹⁴C]Aceticacid, sodiumsalt (5 μCi/well) was added to the media 10minutes after the specimen was added, followed by culturing for further2 hours.

[0449] After the incubation was finished, the supernatant was removedand the cells were washed using PBS(-) (Phosphate buffered saline (Ca²⁺,Mg²⁺ free) twice. Hexane/isopropyl alcohol (3:2, v/v) was added to thecells and the cells were then allowed to stand for 10 minutes to extractintracellular lipid. The extract was transferred to a glass tube andexsiccated under a nitrogen gas stream. Further, the exsiccated extractwas washed with 25 mL of petroleum ether and then dissolved in petroleumether containing the following components: 0.01% squalene, 0.3% freecholesterol, 0.3% cholesterol acetate, 0.1% triolein, 0.01% farnesol and0.3% lanosterol.

[0450] The resulting solution was spotted on a TLC plate to perform anisolating operation. The spot was developed for 10 minutes by usingtoluene/isopropyl ether (1:1, v/v) as the solvents and for further 15minutes by using heptane in place of the above solvent after it wasdried using air.

[0451] After the development was finished, the TLC plate was subjectedto iodine color development. After each position of free cholesterolused as standards was confirmed, the image of the TLC plate wastransferred to a BAS 2000 (Fuji Film) imaging plate by exposureperformed for 16 hours. This transferred image was analyzed using a BAS2000 IP Reader and an Imaging analyzer II to measure radio activitiescontained in the free cholesterol fractions.

[0452] The cholesterol biosynthesis inhibitive activity was expressed bya concentration (IC₅₀) at which 50% of the radio activity of the controlgroup was inhibited.

[0453] The test results based on Test Example 1 (measurement of squalenesynthase inhibitive activity by using a rat liver microsome), TestExample 2 (measurement of cholesterol biosynthesis inhibitive activityin a rat liver cell) are shown below. TABLE 1 Squalene synthase Exampleinhibitive activity IC₅₀ (nM) 1 1.4  7 0.53 9 0.78

[0454] TABLE 2 Cholesterol biosynthesis Example inhibitive activity IC₅₀(nM)  1 0.45 18 0.16

[0455] The compound according to the present invention is very useful asa squalene synthase inhibitor (Table 1) and also as a cholesterolbiosynthesis inhibitor in actual (Table 2). Accordingly, the compoundaccording to the present invention is useful as preventive and curativeagents for a disease on which squalene synthase inhibition orcholesterol biosynthesis inhibition is effective. Also, as described inBr. J. Pharmacol. 2000 September; 131(1): 63-70, the correlation betweenserum cholesterol and triglyceride is disclosed and hence compounds thatinhibit cholesterol biosynthesis are considered to have also a serumtriglyceride decreasing action. From the above results, the compoundaccording to the present invention is useful as a preventive andcurative agent for hyperlipidemia and also as a preventive and curativeagent for arterial sclerosis diseases or ischemic heart diseases.

EXAMPLES

[0456] The present invention will be explained in more detail andconcretely by way of the following Examples, however, the presentinvention is not limited by them. The structural formulae of compoundsin these Examples are listed in the following Table 3.

Production Examples Production Example 12-Benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridinea) 2-Bromo-6-methoxypyridine

[0457] While heating under stirring a mixture of 200 g of2,6-dibromopyridine and 150 ml of methanol on an oil bath at 80° C., 250ml of a 28% sodium methoxide/methanol solution was added dropwiseslowly. The mixture was heated under stirring as it was for 2hours, andafter standing to cool, it was extracted with diethyl ether-water. Theorganic layer was washed with water and brine, and then dried overanhydrous magnesium sulfate. The solvent was removed, to give 150 g ofthe title compound.

[0458]¹H-NMR (CDCl₃) δ ppm=3.94 (3H, s), 6.68 (1H, d, J=7 Hz), 7.06 (1H,d, J=8 Hz), 7.40 (1H, t, J=8 Hz)

b) 2-Benzyl-6-methoxypyridine

[0459] While stirring a mixture of 150 g of 2-bromo-6-methoxypyridine,4.3 g of 1, 3-bis(diphenylphosphino)propanenickel (II) chloride and 500ml of tetrahydrofuran in an ice bath, Grignard reagent prepared from 123ml of benzyl bromide, 30 g of magnesium and 400 ml of diethyl ether wasadded dropwise slowly. After stirring overnight as it was, the mixturewas extracted with an aqueous ammonium chloride solution and hexane. Theorganic layer was washed with water and then with brine, dried overanhydrous magnesium sulfate, and the solvent was removed. The residuewas purified by silica gel column chromatography with (1% ethylacetate/hexane and 1.5% ethyl acetate/hexane), to give 150 g of thetitle compound.

[0460]¹H-NMR(CDCl₃) δppm=3.92(3H, s), 4.03(2H, s), 6.54(1H, d, J=8 Hz),6.65(1H, d, J=7 Hz), 7.18-7.32(5H, m), 7.44(1H, dd, J=7, 8 Hz)

c) 2-Benzyl-6-hydroxypyridine

[0461] A mixture of 59 g of 2-benzyl-6-methoxypyridine and 200 ml of 47%hydrobromic acid was heated under stirring in an oil bath at 100° C. for7 hours. After standing to cool, 250 ml of water was added and theresulting crystals were filtered, washed with water and dried underreduced pressure, to give 38.9 g of the title compound.

[0462]¹H-NMR(DMSO-d₆) δppm=3.78(2H, s), 5.96(1H, d, J=7 Hz), 6.15(1H, d,J=9 Hz), 7.20-7.36(6H, m)

d) 2-Benzyl-6-pyridyl trifluoromethanesulfonate

[0463] A mixture of 10 g of 2-benzyl-6-hydroxypyridine, 23 g ofN-phenyltrifluoromethanesulfonimide, 0.66 g of 4-dimethylaminopyridine,23 ml of triethylamine and 100 ml of dichloromethane was stirred in awater bath at room temperature for 1 hour. The reaction mixture wasevaporated and the residue was subjected to silica gel columnchromatography (2-3% ethyl acetate/hexane). Further, the eluted solutionwas filtered through NH-silica gel (Fuji Silysia Chemical Ltd.) andwashed with 3% ethyl acetate/hexane. The filtrate was evaporated to give11.7 g of the title compound.

[0464]¹H-NMR(CDCl₃) δppm=4.13(2H, s), 6.99(1H, d, J=8 Hz), 7.16(1H, d,J=8 Hz), 7.22-7.34(5H, m), 7.75(1H, t, J=8 Hz)

e) 2-Benzyl-6-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]pyridine

[0465] To a mixture of 11.3 g of 2-benzyl-6-pyridyltrifluoromethanesulfonate, 11.3 g of (3R,4R)-3,4-dihydroxypyrrolidineacetate (synthesized from D-tartaric acid as a starting material, Angew.Chem. Int. Ed. Engl., 23(6), 435, 1984) and 10 ml of N-methylpyrrolidonewas added dropwise 11 ml of 1,8-diazabicyclo[5.4.0]-7-undecene undernitrogen atmosphere in an oil bath at 100° C., followed by heating understirring for 6 hours. After standing to cool, the reaction mixture wasextracted with ethyl acetate-water. The organic layer was washed withwater and brine, dried over anhydrous magnesium sulfate and evaporated.The residue was purified by silica gel column chromatography (ethylacetate), to give 5.35 g of the title compound.

[0466]¹H-NMR(CDCl₃) δppm=3.47(2H, dd, J=2,11 Hz), 3.79(2H, dd, J=4,11Hz), 3.97(2H, s), 4.26-4.30(2H, m), 6.17(1H, d, J=8 Hz), 6.38(1H, d, J=8Hz), 7.19(1H, t, J=7 Hz), 7.26-7.36(5H, m)

f) 2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine

[0467] To a mixture of 5.35 g of2-benzyl-6-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]pyridine and 40 ml oftetrahydrofuran was added dropwise 800 mg of oily (60%) sodium hydridegradually under stirring, and the mixture was stirred as it was for 1hour. Then, 1.24 ml of methyl iodide was added thereto and the resultantmixture was stirred overnight as it was. The reaction mixture wasextracted with ethyl acetate-water, and the organic layer was washedwith water and brine, dried over anhydrous magnesium sulfate andevaporated. The residue was purified by silica gel column chromatography(30% ethyl acetate/hexane), to give 2.18 g of the title compound.

[0468]¹H-NMR(CDCl₃) δppm=3.42(3H, s), 3.47-3.55(2H, m), 3.69-3.78(2H,m), 3.85-3.89(1H, m), 3.97(2H, s), 4.38-4.42(1H, m), 6.17(1H, d, J=8Hz),6.35(1H, d, J=7 Hz), 7.19(1H, t, J=7 Hz), 7.26-7.35(5H, m)

g)2-Benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine

[0469] To a mixture of 3.11 g of2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine and 10ml of N,N-dimethylformamide, while stirring in an ice bath, was addeddropwise 2.5 g of N-iodosuccinimide, and the resultant mixture wasstirred overnight as it was. To this was added sodium sulfite and thereaction mixture was extracted with ethyl acetate-water, and the organiclayer was washed with water and brine, dried over anhydrous magnesiumsulfate and evaporated. The residue was purified by silica gel columnchromatography (30% ethyl acetate/hexane), to give 4.19 g of the titlecompound.

[0470]¹H-NMR(CDCl₃) δppm=3.41(3H, s), 3.42-3.51(2H, m), 3.64-3.71(2H,m), 3.84-3.87(1H, m), 4.19(2H, s), 4.38-4.42(1H, m), 5.98(1H, d, J=8Hz), 7.18(1H, t, J=7 Hz), 7.26(2H, t, J=7 Hz), 7.37(2H, d, J=7 Hz),7.69(1H, d, J=8 Hz)

Production Example 22-Benzyl-3-iodo-6-[(3R,4S)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridinea)2-Benzyl-3-iodo-6-[(3S,4S)-3-(3-nitrobenzenesulfonyl)oxy-4methoxypyrrolidin-1-yl]pyridine

[0471] To a solution of 10.0 g of2-benzyl-3-iodo-6-[(3S,4S)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridineobtained in the same manner as in Production Example 1 by using(3S,4S)-3,4-dihydroxypyrrolidine acetate (Angew. Chem. Int. Ed. Engl.,23(6), 435, 1984) synthesized from L-tartaric acid as a startingmaterial in 150 ml of ethyl acetate were added 300 mg of4-dimethylaminopyridine, 10 ml of triethylamine and 9.7 g of3-nitrobenzenesulfonyl chloride, followed by stirring at roomtemperature for 3 days. The reaction mixture was first filtered through50 g of silica gel and washed with ethyl acetate. The filtrate wasfurther filtered through 50 g of NH-silica gel and washed with ethylacetate. The filtrate was concentrated, to give 14.6 g of the titlecompound.

[0472]¹H-NMR(CDCl₃) δppm=3.38(3H, s), 3.48(1H, d, J=12 Hz),3.58-3.73(3H, m), 4.08-4.20(3H, m), 5.10-5.14(1H, m), 5.92(1H, d, J=8Hz), 7.18(1H, t, J=7 Hz), 7.25(2H, t, J=7 Hz), 7.32(2H, d, J=7 Hz),7.69(1H, d, J=8 Hz), 7.73(1H, t, J=8 Hz), 8.21(1H, d, J=8 Hz), 8.49(1H,d, J=8 Hz), 8.75(1H, s)

b) 2-Benzyl-3-iodo-6-[(3R,4S)-3-acetoxy-4-methoxypyrrolidin-1yl]pyridine

[0473] To a mixture of 7.9 g of cesium carbonate and 15 ml of dimethylsulfoxide was added 4.2 ml of acetic acid. After foaming ceased, amixture of 14.4 g of2-benzyl-3-iodo-6-[(3S,4S)-3-(3-nitrobenzenesulfonyl)oxy-4-methoxypyrrolidin-1-yl]pyridineand 35 ml of dimethyl sulfoxide was added and the resultant mixture washeated under stirring under nitrogen atmosphere in an oil bath at 70° C.for 6 hours. After the reaction mixture was cooled, it was extractedwith ethyl acetate-water. The organic layer was washed with water andbrine, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by silica gel column chromatography (10-15% ethylacetate/hexane), to give 7.5 g of the title compound. ¹H-NMR(CDCl₃)δppm=2.12(3H, s), 3.42(3H, s), 3.37-3.73(4H, m), 4.04(1H, dt, J=4, 6Hz), 4.19(2H, s), 5.42-5.47(1H, m), 5.96(1H, d, J=8 Hz), 7.19(1H, t, J=7Hz), 7.27(2H, t, J=7 Hz), 7.38(2H, d, J=7 Hz), 7.70(1H, d, J=8 Hz)

c)2-Benzyl-3-iodo-6-[(3R,4S)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine

[0474] To a mixture of 7.5 g of2-benzyl-3-iodo-6-[(3R,4S)-3-acetoxy-4-methoxypyrrolidin-1-yl]pyridineand 30 ml of methanol was added 0.33 ml of 28% methanol solution ofsodium methoxide and the resultant mixture was stirred under nitrogenatmosphere at room temperature for 30 minutes. Water was added to thereaction mixture, which was extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (20-50% ethyl acetate/hexane), to give 6.7 g of the titlecompound.

[0475]¹H-NMR(CDCl₃) δppm=2.63(1H, d, J=5 Hz),3.38-3.67(4H, m), 3.47(3H,s), 3.93(1H, q, J=5 Hz), 4.18(2H, s), 4.41(1H, quint., J=5 Hz), 5.96(1H,d, J=9 Hz), 7.18(1H, t, J=7 Hz), 7.26(2H, t, J=7 Hz), 7.37(2H, d, J=7Hz), 7.69(1H, d, J=9 Hz)

Production Example 3 2-Benzyl-3-methoxymethyloxy-6-iodopyridine a)2-Bromo-3-methoxymethyloxypyridine

[0476] 50 g of 2-bromo-3-hydroxypyridine was suspended in 200 ml oftetrahydrofuran, to which 33 ml of chloromethyl methyl ether was added.The mixture was cooled to −20° C. and 17 g of 60% oily sodium hydridewas portionwise added while stirring. After the addition of sodiumhydride, the refrigerant was removed and the mixture was stirred at roomtemperature for 3.5 hours. In an ice bath, ice water was portionwiseadded and the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with brine and dried over anhydrous sodiumsulfate. The solvent was removed, and the residue was purified by silicagel column chromatography (10-15% ethyl acetate/hexane), to give 35 g ofthe title compound.

[0477]¹H-NMR(CDCl₃) δppm=3.53(3H, s), 5.28(2H, s), 7.21(1H, dd, J=4.6,8.2 Hz), 7.43(1H, dd, J=1.6, 8.2 Hz), 8.05(1H, dd, J=1.6, 4.6 Hz)

b) 2-Benzyl-3-methoxymethyloxypyridine

[0478] While stirring a mixture of 35 g of2-bromo-3-methoxymethyloxypyridine, 5 g of1,3-bis(diphenylphosphino)propanenickel (II) chloride and 200 ml oftetrahydrofuran under ice-cooling, a diethyl ether solution ofbenzylmagnesium bromide prepared from 38 ml of benzyl bromide, 8 g ofmagnesium and 250 ml of anhydrous diethyl ether was slowly addeddropwise thereinto under nitrogen atmosphere. After stirring for 4.5hours, a saturated aqueous ammonium chloride solution was added thereto,and the mixture was extracted with ethyl acetate. The organic layer waswashed with brine and dried over anhydrous sodium sulfate. The solventwas removed, and the residue was purified by silica gel columnchromatography (8-20% ethyl acetate/hexane), to give 27 g of the titlecompound.

[0479]¹H-NMR(CDCl₃) δppm=3.34(3H, s), 4.21(2H, s), 5.17(2H, s)7.11-7.38(7H, m), 8.20(1H, dd, J=1.3, 4.8 Hz)

c) 2-Benzyl-3-methoxymethyloxy-6-iodopyridine

[0480] To 27 g of 2-benzyl-3-methoxymethyloxypyridine was added 60 ml oftrifluoroacetic acid, and the mixture was stirred at room temperaturefor 2 hours and further heated under stirring in an oil bath at 50° C.for 1 hour. The reaction mixture was added to an ice-cooled aqueouspotassium carbonate solution and the resulting crystals were collectedby filtration and dried under reduced pressure. To the resultingcrystals were added 19 g of sodium iodide, 5 g of sodium hydroxide and200 ml of methanol, and 158 ml of an aqueous 5% sodium hypochloritesolution was added dropwise over 30 minutes while stirring in an icebath. After stirring overnight as it was, 60 ml of 5 N hydrochloric acidand further a saturated aqueous sodium thiosulfate solution were addedthereto and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine and dried over anhydrous sodium sulfate. Thesolvent was removed, and the resulting crystals were collected byfiltration and dried under reduced pressure, to give 17 g of2-benzyl-3-hydroxy-6-iodopyridine.

[0481] 12 g of 2-benzyl-3-hydroxy-6-iodopyridine was dissolved in 50 mlof tetrahydrofuran and 3.8 ml of chloromethyl methyl ether was addedthereto. While stirring in an ice bath, 2 g of 60% oily sodium hydridewas portionwise added to the mixture. After the addition of sodiumhydride, the refrigerant was removed and the mixture was stirred at roomtemperature for 2.5 hours. Thereafter, in an ice bath, ice water wasportionwise added thereto, and the mixture was extracted with ethylacetate. The organic layer was washed with brine and dried overanhydrous sodium sulfate. The solvent was removed and the residue waspurified by silica gel column chromatography (15% ethyl acetate/hexane),to give 13 g of the title compound.

[0482]¹H-NMR(CDCl₃) δppm=3.28(3H, s), 4.14 (2H, s), 5.11(2H, s),7.04(1H, d, J=8.4 Hz), 7.14-7.30(5H, m), 7.48(1H, d, J=8.4 Hz)

Production Example 4 2-Benzyl-1-methoxymethyloxy-4-iodobenzene a)2-Benzyl-1-hydroxy-4-iodobenzene

[0483] 6.87 g of 2-benzylphenol, 7.2 g of sodium iodide and 1.7 g ofsodium hydroxide were added to 60 ml of methanol and while stirring inan ice bath, 50 ml of an aqueous 5% sodiumhypochlorite solution wasadded dropwise to the mixture over 30 minutes. The temperature wasslowly returned to room temperature and the stirring was continuedovernight. Water was added to the reaction mixture, which then wasextracted with ethyl acetate, washed with brine and then dried overanhydrous magnesium sulfate. The solvent was removed and the residue waspurified by silica gel column chromatography (30% ethyl acetate/hexane),to give 10.1 g of the title compound.

[0484]¹H-NMR(CDCl₃) δppm=3.92(2H, s), 4.91 (1H, s), 6.56(1H, d, J=8.4Hz) 7.15-7.30(5H, m), 7.37-7.43(2H, m)

b) 2-Benzyl-1-methoxymethyloxy-4-iodobenzene

[0485] 10.1 g of 2-benzyl-1-hydroxy-4-iodobenzene and 3 ml ofchloromethyl methyl ether were added to 100 ml of tetrahydrofuran andwhile stirring on an ice bath, 1.45 g of 60% (oily) sodium hydride wasadded dropwise to the mixture. After stirring for 2 hours, water wasadded to the reaction mixture, which then was extracted with ethylacetate, washed with saturated brine and thereafter dried over anhydrousmagnesium sulfate. The solvent was removed, and the residue was purifiedby silica gel column chromatography with 10% ethyl acetate/hexane, togive 8.7 g of the title compound.

[0486]¹H-NMR(CDCl₃) δppm=3.33(3H, s), 3.92(2H, s), 5.13(2H, s), 6.84(1H,d, J=8.4 Hz), 7.14-7.30(5H, m), 7.41(1H, d, J=2 Hz), 7.45(1H, dd, J=8.4Hz)

Production Example 5 2-Benzyl-4-(2-pyrrolidinon-1-yl)phenyltrifluoromethanesulfonate a)2-Benzyl-1-methoxymethyloxy-4-(2-pyrrolidinon-1-yl)benzene

[0487] A mixture of 560 mg of 2-benzyl-1-methoxymethyloxy-4-iodobenzene(Production Example 4), 5 ml of 2-pyrrolidone, 90 mg of copper iodide(I), and 400 mg of anhydrous potassium carbonate was heated understirring under nitrogen atmosphere on an oil bath at 140° C. for 8hours. Aqueous ammonia was added to the reaction mixture, and themixture was extracted with ethyl acetate. Then it was successivelywashed with water and brine, dried over anhydrous magnesium sulfate andthen evaporated, to give 505 mg of the title compound.

[0488]¹H-NMR(CDCl₃) δppm=2.07-2.17(2H, m), 2.57(2H, t, J=8 Hz), 3.35(3H,s), 3.78(2H, t, J=7 Hz), 4.00(2H, s), 5.13(2H, s), 7.07(1H, d, J=8 Hz),7.14-7.30(5H, m), 7.35-7.40(2H, m)

b) 2-Benzyl-4-(2-pyrrolidinon-1-yl)phenol

[0489] A mixture of 505 mg of2-benzyl-1-methoxymethyloxy-4-(2-pyrrolidinon-1-yl)benzene and 5 ml oftrifluoroacetic acid was stirred at room temperature for 1 hour. Thereaction mixture was evaporated, and the residue was purified by silicagel column chromatography with 30-60% ethyl acetate/hexane, to give 320mg of the title compound.

[0490]¹H-NMR(CDCl₃) δppm=2.07-2.17(2H, m), 2.58(2H, t, J=8 Hz), 3.77(2H,t, J=7 Hz), 3.98(2H, s), 5.28(1H, brs), 6.74(1H, d, J=9 Hz),7.19-7.32(7H, m)

c) 2-Benzyl-4-(2-pyrrolidinon-1-yl)phenyl trifluoromethanesulfonate

[0491] 320 mg of 2-benzyl-4-(2-pyrrolidinon-1-yl)phenol, 520 mg ofN-phenyltrifluoromethanesulfonimide, 15 mg of 4-dimethylaminopyridineand 0.5 ml of triethylamine were dissolved in 2.5 ml of dichloromethane,followed by stirring at room temperature overnight. The reaction mixturewas purified by silica gel column chromatography with 30% ethylacetate/hexane, to give 450 mg of the title compound.

[0492]¹H-NMR(CDCl₃) δppm=2.09-2.18(2H,m),2.59(2H, t, J=8 Hz),3.76(2H, t,J=7 Hz), 4.08(2H, s), 7.17-7.34(6H, m), 7.48(1H, d, J=3 Hz) 7.61(1H, dd,J=9 Hz)

Production Example 6 2-Benzyl-3-hydroxy-6-(2-pyrrolidinon-1-yl)pyridine

[0493] This was synthesized in the same manner as in Production Example5-a and b except that 2-benzyl-3-methoxymethyloxy-6-iodopyridine(Production Example 3) was used as a starting material.

[0494]¹H-NMR(CDCl₃) δppm=2.06-2.15(2H, m), 2.64(2H, t, J=8 Hz), 4.08(2H,t, J=7 Hz), 4.13(2H, s), 4.69(1H, brs), 7.12(1H, d, J=9 Hz),7.19-7.32(5H, m), 8.12(1H, d, J=9 Hz)

Production Example 72-Benzyl-6-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinon-1-yl]-3-pyridyltrifluoromethanesulfonate (A) and2-benzyl-6-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinon-1-yl]-3-pyridyltrifluoromethanesulfonate (B) a)2-Benzyl-3-methoxymethyloxy-6-[(3R,4R)-3,4-dimethylmethylenedioxy-2-pyrrolidinon-1-yl]pyridine

[0495] 3.6 g of 2-benzyl-3-methoxymethyloxy-6-iodopyridine (ProductionExample 3), 1.5 g of (3R,4R)-3,4-dimethylmethylenedioxy-2-pyrrolidinonesynthesized by the known method as described in the literature document(J. Org. Chem., 1969, 34, 675.), 1.1 g of copper iodide (I), and 3.3 gof potassium carbonate were suspended in 20 ml of1-methyl-2-pyrrolidone, followed by heating under stirring in an oilbath at 140° C. for 20 minutes under nitrogen atmosphere. After standingto cool, ethyl acetate and aqueous ammonia were added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith brine and dried over anhydrous sodium sulfate. The solvent wasremoved, and the residue was purified by silica gel columnchromatography with 20-50% ethyl acetate/hexane, to give 2 g of thetitle compound.

[0496]¹H-NMR(CDCl₃) δppm=1.42(3H, s), 1.46(3H, s), 3.37(3H, s),4.08-4.13(3H, m), 4.26(1H, d, J=13 Hz), 4.80(2H, s), 5.14(2H, dd, J=6.8,10 Hz),7.17-7.31(5H, m), 7.42(1H, d, J=9.0 Hz), 8.22(1H, d, J=9.0 Hz)

b) 2-Benzyl-6-[(3R,4R)-3,4-dimethylmethylenedioxy-2-pyrrolidinon-1-yl]-3-pyridyl trifluoromethanesulfonate

[0497] To 2 g of2-benzyl-3-methoxymethyloxy-6-[(3R,4R)-3,4-dimethylmethylenedioxy-2-pyrrolidinon-1-yl]pyridine was added 5 ml of trifluoroaceticacid, followed by stirring at room temperature for 6 hours. Thereafter,the reaction mixture was neutralized with an aqueous potassium carbonatesolution and extracted with ethyl acetate. Further, the organic layerwas washed with brine and dried over anhydrous sodium sulfate. Thesolvent was removed and the resulting residue was dissolved in 30 ml ofdichloromethane. 2.1 g of N-phenyltrifluoromethanesulfonimide, 192 mg of4-dimethylaminopyridine and 0.8 ml of triethylamine were added thereto,followed by stirring at room temperature for 1 hour. Then, the solventwas removed, and the residue was purified by silica gel columnchromatography with 25% ethyl acetate/hexane, to give 2.2 g of the titlecompound.

[0498]¹H-NMR(CDCl₃) δppm=1.42(3H, s), 1.46(3H, s), 4.03(1H, dd, J=4.0,13 Hz), 4.18(2H, s), 4.23(1H, d, J=13 Hz), 4.79-4.83(2H, m),7.20-7.42(5H, m), 7.60(1H, d, J=9.2 Hz), 8.44(1H, d, J=9.2 Hz)

c) 2-Benzyl-6-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinon-1-yl]pyrid yltrifluoromethanesulfonate (A) and2-Benzyl-6-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinon-1-yl]-3-pyridyltrifluoromethanesulfonate (B)

[0499] 2.2 g of2-benzyl-6-[(3R,4R)-3,4-dimethylmethylenedioxy-2-pyrrolidinon-1-yl]-3-pyridyl trifluoromethanesulfonate was dissolved in 20 ml ofmethanol and 5 ml of 5 N hydrochloric acid was added, followed bystirring at room temperature for 1.5 hours and then in an oil bath at50° C. for 2 hours. After standing to cool, the reaction mixture wasneutralized with an aqueous potassium carbonate solution and extractedwith ethyl acetate. Further, the organic layer was washed with brine anddried over anhydrous sodium sulfate. The solvent was removed and theresulting residue was dissolved in 20 ml of acetonitrile. 1.5 ml ofmethyl iodide and 5.6 g of silver (I) oxide were added thereto, followedby heating under stirring in an oil bath at 60° C. for 1.5 hours. Theinsoluble matters were filtered through Celite. The filtrate wasevaporated and separation, and separated and purified and by silica gelcolumn chromatography with 33-50% ethyl acetate/hexane as an elutionsolvent, to give 685 g of the title compound (A) and 599 mg of the titlecompound (B).

[0500] Compound (A): ¹H-NMR(CDCl₃) δppm=3.47(3H, s), 3.69(3H, s),3.80(1H, dd, J=3.8, 12 Hz), 4.07-4.21(5H, m), 7.22-7.29(5H, m), 7.58(1H,d, J=9.2 Hz), 8.38(1H, d, J=9.2 Hz)

[0501] Compound (B): ¹H-NMR(CDCl₃) δppm=3.48(1H, d, J=4.6 Hz), 3.74(3H,s), 3.86(1H, dd, J=13 Hz, 4.0 Hz), 4.06-4.18(4H, m), 4.54-4.57(1H, m),7.24-7.30(5H, m), 7.59(1H, d, J=9.0 Hz), 8.37(1H, d, J=9.0 Hz)

Production Example 82-Benzyl-4[(3R,4R)-3,4-dimethoxy-2-pyrrolidinon-1-yl]phenyltrifluoromethanesulfonate

[0502] This was synthesized in the same manner as in Production Example7 except that 2-benzyl-3-methoxymethyloxy-4-iodobenzene (ProductionExample 4) was used as a starting material.

[0503]¹H-NMR(CDCl₃) δppm=3.48(3H, s), 3.68(3H, s), 3.74(2H, d, J=3.2 Hz)4.01(1H, d, J=5.2 Hz), 4.08(2H, s), 4.10-4.17(1H, m), 7.15-7.35(6H, m),7.48(1H, d, J=3 Hz), 7.62(1H, dd, J=3, 9 Hz)

Production Example 92-Benzyl-4-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinon-1-yl]phenyltrifluoromethanesulfonate

[0504] This was synthesized in the same manner as in Production Example7 except that 2-benzyl-1-methoxymethyloxy-4-iodopyridine (ProductionExample 4) was used as a starting material.

[0505]¹H-NMR(CDCl₃) δppm=2.75(1H, brs), 3.70(1H, dd, J=1, 10 Hz),3.72(3H, s), 3.79(1H, dd, J=4, 10 Hz), 4.01(1H, d, J=5 Hz), 4.07(2H, s),4.52-4.56(1H, m), 7.16-7.34(6H, m), 7.47(1H, d, J=3 Hz), 7.64(1H, dd,J=3, 9 Hz)

Production Example 10(3R,4S)-1-(3-Benzylphenyl)-3,4-dihydroxypyrrolidine a)1-(3-Bromophenyl)-2,5-dihydropyrrole

[0506] In an ice bath, 26 ml of methanesulfonyl chloride was addeddropwise in to a mixture of 10 g of cis-2-buten-1,4-diol, 63 ml oftriethylamine and 1000 ml of ethyl acetate, followed by stirring at thesame temperature for 3 hours. Then, the insoluble matters were removedby filtration. The filtrate was further filtered through silica gel andwashed with ethyl acetate. Then, the filtrate was evaporated, to give21.4 g of cis-1,4-bis(methanesulfonyloxy)-2-butene.

[0507] Then, a mixture of 15 g of thecis-1,4-bis(methanesulfonyloxy)-2-butene, 10 g of 3-bromoaniline, 24 gof anhydrous potassium carbonate and 70 ml of N,N-dimethylformamide wasstirred at room temperature overnight. The reaction mixture wasextracted with ethyl acetate-water, and the organic layer was washedwith water and brine, dried over anhydrous magnesium sulfate and thenevaporated. The residue was purified by silica gel column chromatographywith 5% ethyl acetate/hexane, to give 6.6 g of the title compound.

[0508]¹H-NMR(CDCl₃) δppm=4.08(4H, s), 5.94(2H, s), 6.43(1H, dd, J=2, 7Hz), 6.65(1H, t, J=2 Hz), 6.78(1H, dd, J=2, 7 Hz), 7.08(1H, t, J=7 Hz)

b) 1-(3-Benzylphenyl)-2,5-dihydropyrrole

[0509] To a mixture of 6.6 g of 1-(3-bromophenyl)-2,5-dihydropyrrole,800 mg of 1,3-bis(diphenylphosphino)propanenickel (II) chloride and 40ml of tetrahydrofuran was added dropwise 22 ml of a 2.0 Mtetrahydrofuran solution of benzyl magnesium chloride, followed bystirring overnight as it was. The reaction mixture was separated with asaturated aqueous ammonium chloride solution-ethyl acetate, and theorganic layer was washed with water and brine, dried over anhydrousmagnesium sulfate and then evaporated. The residue was purified bysilica gel column chromatography with 1% ethyl acetate/hexane, to give2.1 g of the title compound.

[0510]¹H-NMR(CDCl₃) δppm=3.95(2H, s), 4.08(4H, s), 5.93(2H, s),6.35-6.41(2H,m), 6.52(1H, br.d, J=7 Hz), 7.14-7.30(6H, m) c)(3R,4S)-1-(3-Benzylphenyl)-3,4-dihydroxypyrrolidine

[0511] While stirring 20 ml of an acetone solution of 2.1 g of1-(3-benzylphenyl)-2,5-dihydropyrrole on an ice bath, 2.2 ml of a 50%aqueous solution of N-methylmorpholine-N-oxide, 4 ml of water and 0.5 mlof a 2.5% t-butanol solution of osmium tetroxide were successively addedthereto, followed by stirring as it was at room temperature overnight.After adding 2 ml of a 1 M aqueous solution of sodium thiosulfate, thereaction mixture was extracted with ethyl acetate-water. The organiclayer was washed with water and brine, dried over anhydrous magnesiumsulfate and evaporated. The residue was purified by silica gel columnchromatography with 10-50% ethyl acetate/hexane, to give 1.15 g of thetitle compound.

[0512]¹H-NMR(CDCl₃) δppm=2.47(2H, br.s), 3.27(2H, dd, J=4, 10 Hz),3.53(2H, dd, J=6, 10 Hz), 3.92(2H, s), 4.14(2H, br.s), 6.34-6.41(2H, m),6.56(1H, d, J=7 Hz), 7.12-7.30(6H, m)

Production Example 11(3R,4S)-1-(3-Benzylphenyl)-3,4-dimethoxypyrrolidine

[0513] While stirring a mixture of 270 mg of(3R,4S)-1-(3-benzylphenyl)-3,4-dihydroxypyrrolidine (Production Example10) and 5 ml of N,N-dimethylformamide in an ice bath, 0.15 ml ofiodomethane and 100 mg of sodium hydride were added thereto, followed bystirring at the same temperature for 3 hours. The reaction mixture wasextracted with ethyl acetate-water, and the organic layer was washedwith water and brine, dried over anhydrous magnesium sulfate andevaporated. The residue was purified by silica gel column chromatographywith 5-15% ethyl acetate/hexane, to give 250 mg of the title compound.

[0514]¹H-NMR(CDCl₃) δppm=3.38(2H, dd, J=4, 10 Hz), 3.44-3.49(2H, m),3.46(6H, s), 3.93(2H, s), 3.97-4.02(2H, m), 6.35-6.41(2H, m), 6.53(1H,d, J=7 Hz), 7.12-7.30(6H, m)

Production Example 121-(3-Benzylphenyl)-cis-3-hydroxy-4-methoxypyrrolidine

[0515] This was synthesized in the same manner as in Production Example11 except that 1 equivalent of each of sodium hydride and iodomethanewere used to (3R,4S)-1-(3-Benzylphenyl)-3,4-dihydroxypyrrolidine(Production Example 10).

[0516]¹H-NMR(CDCl₃) δppm=2.73(1H, d, J=6 Hz), 3.24-3.36(2H, m),3.45-3.54(5H, m), 3.91-3.97(3H, m), 4.37-4.43(1H, m), 6.34-6.41(2H, m),6.54(1H, d, J=7 Hz), 7.11-7.30(6H, m)

Production Example 131-(3-Bromophenyl)-trans-3-hydroxy-4-methoxypyrrolidine a)Cis-oxirane-2,3-dimethanol

[0517] To a mixture of 4 g of cis-2-buten-1,4-diol and 100 ml and ethylacetate was added 10 g of m-chloroperbenzoic acid (70% content) underice-cooling, followed by stirring as it was at room temperature for 4days. The reaction mixture was concentrated and the resultingm-chlorobenzoic acid was separated by filtration, and then 2.3 g ofcrystals of the entitled compound was obtained from the mother liquor.

[0518]¹H-NMR(CDCl₃) δppm=2.07(2H, m), 3.24-3.32(2H, m), 3.78-3.94(4H, m)

b) Cis-2,3-bis(methanesulfonyloxymethyl)oxirane

[0519] To a mixture of 2.3 g of cis-oxirane-2,3-dimethanol and 200 ml ofethyl acetate was added 9.3 ml of triethylamine and then 4.3 ml ofmethanesulfonyl chloride under ice-cooling, followed by stirring at thesame temperature for 4 hours. The reaction mixture was filtered throughsilica gel and washed with ethyl acetate. Thereafter, the filtrate wasevaporated, to give 5.4 g of the title compound.

[0520]¹H-NMR(CDCl₃) δppm=3.11(6H, s), 3.44-3.48(2H, m), 4.35(2H, dd,J=6, 12 Hz), 4.46(2H, dd, J=4, 12 Hz)

c) 1-(3-Bromophenyl)-3,4-epoxypyrrolidine

[0521] A mixture of 5.4 g ofcis-2,3-bis(methanesulfonyloxymethyl)oxirane, 2 ml of 3-bromoaniline,4.3 g of anhydrous potassium carbonate and 30 ml ofN,N-dimethylformamide was stirred under nitrogen atmosphere at 60° C.for 2 hours and at 110° C. for 2 hours. The reaction mixture wasextracted with ethyl acetate-water, and the organic layer was washedwith water and brine, dried over anhydrous magnesium sulfate and thenevaporated. The residue was purified by silica gel column chromatographywith 5-10% ethyl acetate/hexane, to give 420 mg of the title compound.

[0522]¹H-NMR(CDCl₃) δppm=3.30(2H, d, J=12 Hz), 3.69(2H, d, J=12 Hz),3.87(2H, s), 6.41(1H, dd, J=2, 8 Hz), 6.63(1H, t, J=2 Hz), 6.80(1H, dd,J=2, 8 Hz), 7.05(1H, t, J=8 Hz)

d) 1-(3-Bromophenyl)-trans-3-hydroxy-4-methoxypyrrolidine

[0523] A mixture of 420 mg of 1-(3-bromophenyl)-3,4-epoxypyrrolidine,0.7 ml of a 28% methanol solution of sodium methoxide and 5 ml ofmethanol was stirred at 50° C. for 4 hours. The reaction mixture wasextracted with ethyl acetate-water, and the organic layer was washedwith water and brine, dried over anhydrous magnesium sulfate and theevaporated. The residue was purified by silica gel column chromatographywith 10-30% ethyl acetate/hexane, to give 460 mg of the entitledcompound.

[0524]¹H-NMR(CDCl₃) δppm=1.85(1H, d, J=5 Hz), 3.22-3.30(2H, m), 3.41(3H,s), 3.55-3.64(2H, m), 3.86-3.89(1H, m), 4.38-4.43(1H, m), 6.46(1H, dd,J=2, 8 Hz), 6.68(1H, t, J=2 Hz), 6.80(1H, dd, J=2, 8 Hz), 7.06(1H, t,J=8 Hz)

Production Example 142-(4-Bromophenyl)-6-methyl-1,3,6,2-dioxyazaborocane

[0525] 107 g of 4-bromophenylboric acid and 92 ml ofN-methyldiethanolamine were suspended in 1000 ml of toluene, followed byheating under reflux for 2 hours while removing water. The toluene wasremoved and the resulting solid matter was collected by filtered andwashed with hexane-toluene. The collected solid was recrystallized fromtoluene, to give 128 g of the title compound.

[0526]¹H-NMR(CDCl₃) δppm=2.32(3H, s), 2.95-3.04(2H, m), 3.16-3.24(2H,m), 4.09-4.17(2H, m), 4.17-4.25(2H, m), 7.42(2H, d, J=8.4 Hz), 7.50(2H,d, J=8.4 Hz)

Production Example 15 1-tert-Butoxycarbonyl-3-ethynyl-3-piperidinol a)1-tert-Butoxycarbonylpiperidin-3-one

[0527] 10 g of 3-hydroxypiperidine and 15 ml of triethylamine weredissolved in 100 ml of tetrahydrofuran. While stirring in an ice bath, asolution of 22.9 g of di-tert-butyl dicarbonate in 50 ml oftetrahydrofuran was added dropwise thereto. After completion of thedropwise addition, the reaction mixture was stirred for 1 hour and thenevaporated. 25 ml of triethylamine was added to the residue and asolution of 25 g of pyridine trioxide-sulfur complex in 100 ml ofdimethyl sulfoxide was added dropwise thereto, followed by stirring for2 hours. Ice water was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was successivelywashed with an aqueous hypochlorous acid solution, water and brine,dried over anhydrous magnesium sulfate and evaporated. The residue waspurified by silica gel column chromatography with 30% ethylacetate/hexane, to give 13.1 g of the title compound.

[0528]¹H-NMR(CDCl₃) δppm=1.47(9H, s), 1.94-2.02(2H, m), 2.47(2H, t, J=7Hz), 3.59(2H, t, J=6 Hz), 4.00(2H, s)

b) 1-tert-Butoxycarbonyl-3-ethynyl-3-piperidinol

[0529] In a dry ice-acetone bath, 40 ml of a 1.6 M hexane solution ofn-butyllithium was added dropwise to a solution of 6.07 g oftrimethylsilylacetylene in 100 ml of tetrahydrofuran. After thetemperature was once elevated to 0° C., the mixture was cooled again ina dry ice-acetone bath and a solution of 5.97 g of1-tert-butoxycarbonylpiperidin-3-one in 50 ml of tetrahydrofuran wasadded dropwise thereto. After 1 hour, aqueous ammonia chloride was addedthereto, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate andthen evaporated. The residue was purified by silica gel columnchromatography with 30% ethyl acetate/hexane. To the resulting compoundwere added 10 g of anhydrous potassium carbonate and 100 ml of methanol,followed by stirring for 2 hours. Water was added thereto, and themixture was extracted with ethyl acetate, dried over anhydrous magnesiumsulfate and evaporated, to give 4.8 g of the title compound.

[0530]¹H-NMR(DMSO-d₆) δppm=1.39(9H, s), 1.44-1.65(3H, m), 1.76-1.89(1H,m), 2.80-3.76(5H, m), 5.68(1H, s)

Production Example 16 1-Benzyl-3-(2-propynyloxy)pyrrolidine

[0531] On an ice bath, 233 mg of sodium hydride was added to a mixtureof 948 mg of 1-benzyl-3-pyrrolidinol and 10 ml of N,N-dimethylformamideand the mixture was stirred at room temperature for 1 hour. There actionmixture was cooled to −40° C. and 495 μl of propargyl bromide was addedthereto. The temperature was elevated to room temperature and water andethyl acetate were added to the reaction mixture. The organic layer wasseparated, washed with water and brine, dried over anhydrous magnesiumsulfate and the solvent was removed. The residue was purified byNH-silica gel column chromatography with 15% ethyl acetate/hexane, togive 507 mg of the title compound.

[0532]¹H-NMR(CDCl₃) δppm=1.82-1.86(1H, m), 2.09-2.14(1H, m), 2.39(1H,s), 2.49-2.59(2H, m), 2.65-2.71(1H, m), 2.77-2.80(1H, m), 3.58-3.67(2H,m), 4.10-4.12(2H, m), 4.25-4.28(1H, m), 7.23-7.34(5H, m)

Production Example 17 1-Acetoxy-1-ethynylcyclohexane

[0533] 12.1 g of 1-ethylnyl-1-cyclohexanol was dissolved in 200 ml ofdichloromethane and 18.9 ml of acetic anhydride was added dropwise tothe solution in an ice bath. Then, 2 ml of a 1 M dichloromethanesolution of trimethylsilyl triflate was added dropwise to the solution.After stirring for 1 hour and 15 minutes, ice was added to the reactionmixture and a saturated aqueous sodium hydrogen carbonate solution wasadded thereto to basify the reaction mixture. After further stirring for1 hour and 30 minutes, it was extracted with dichloromethane. Afteradding 8.1 mL of methanol to the organic layer, it was successivelywashed with a saturated aqueous sodium hydrogen carbonate solution andwater, and dried over anhydrous magnesium sulfate. The solvent wasevaporated, to give 22.2 g of the title compound.

[0534]¹H-NMR(CDCl₃) δppm=1.28-1.38(1H, m), 1.47-1.57(1H, m),1.58-1.66(4H, m), 1.80-1.89(2H, m), 2.04(3H, s), 2.09-2.16(2H, m),2.59(1H, s)

Production Example 18 1-(1-Ethynylcyclohexyl)piperidine

[0535] 7.0 g of 1-acetoxy-1-ethynylcyclohexane (Production Example 17)was dissolved in 140 ml of tetrahydrofuran, and after 20.8 ml ofpiperidine was added dropwise thereto at room temperature, 208 mg ofcopper chloride (I) was added to the resulting yellow transparentsolution. The resulting mixture was stirred in an oil bath at 95° C. for2 hours. The reaction mixture was left to stand to cool to roomtemperature, 200 ml of diethyl ether was added thereto and extractedwith 100 ml of an aqueous 2 N hydrochloric solution twice. Afteraddition of about 200 ml of ice to the resultant acidic solution, sodiumhydroxide was added to the solution until the solution became basic(pH=10). The solution was extracted with 100 ml of dichloromethanetwice. The organic layer was dried over anhydrous magnesium sulfate. Thesolvent was removed, to give a brown solid. To the solid was addedhexane and washed, and the solid was collected by filtration, to give700 mg of the title compound.

[0536]¹H-NMR(CDCl₃) δppm=1.14-1.26(1H, m), 1.38-1.73(12H, m),1.79-1.88(1H, m), 1.96-2.04(2H, m), 2.32(1H, s), 2.60-2.66(4H, m)

Production Example 19 1-Ethynyl-N-methylcyclohexylamine

[0537] This was synthesized in the same manner as in Production Example18 except that 1-acetoxy-1-ethynylcyclohexane (Production Example 17)and a 40% methylamine/methanol solution were used.

[0538]¹H-NMR(DMSO-d₆) δppm=1.08-1.75(10H, m), 2.24(3H, s), 3.12(1H, s)

Production Example 20 2-[(1-Ethynylcyclohexyl)amino]ethanol

[0539] This was synthesized in the same manner as in Production Example18 except that 1-acetoxy-1-ethynylcyclohexane (Production Example 17)and ethanolamine were used.

[0540]¹H-NMR(DMSO-d₆) δppm=1.10-1.75(10H, m), 2.64(2H, t, J=6 Hz),3.12(1H, s), 3.43(2H, t, J=6 Hz), 4.47(1H, brs)

Production Example 21 2-Ethynylbicyclo[2.2.1]heptan-2-ol

[0541] 500 mg of norcamphor was dissolved in 6 ml of tetrahydrofuran andthe solution was added dropwise in a suspension of 543 mg of lithiumacetylide-ethylenediamine complex in tetrahydrofuran at roomtemperature, and the resulting reaction mixture was stirred for 18hours. After water was added to the resulting reaction mixture, it wasevaporated while maintaining the temperature of the water bath at 25° C.The residue was extracted with ethyl acetate twice. The resultingorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and evaporated, to give 523 mg of the title compound.

[0542]¹H-NMR(DMSO-d₆) δppm=1.11-2.20 (10H, m), 3.23 (1H, s), 5.35 (1H,s)

Production Example 22 (3R)-3-Ethynyl-3-quinuclidinol a)(3R)-3-Ethynyl-3-quinuclidinol.L-(+)-tartrate

[0543] 15.1 g of 3-ethynyl-3-quinuclidinol and 15 g of L-(+)-tartaricacid were dissolved under heating in 300 ml of methanol. After standingto cool, the resulting crystals were collected by filtration andrecrystallized from methanol for three times, to give 2.07 g of thetitle compound.

[0544]¹H-NMR(DMSO-d₆) δppm=1.45-1.54(1H, m), 1.68-1.78(1H, m),1.83-2.03(3H, m), 2.83-3.01(5H, m), 3.21(1H, dd, J=2, 14 Hz), 3.50(1H,s), 4.05(2H, s)

b) (3R)-3-Ethynyl-3-quinuclidinol

[0545] 15.6 g of (3R)-3-Ethynyl-3-quinuclidinol.L-(+)-tartrate wasdissolved in 150 ml of water and 20 g of anhydrous potassium carbonatewas gradually added dropwise to the solution under stirring. Theresulting crystals were collected by filtration, washed with water anddried, to give 6.88 g of the title compound.

[0546]¹H-NMR(DMSO-d₆) δppm=1.20-1.30(1H, m), 1.47-1.55(1H, m),1.70-1.90(3.H, m), 2.54-2.70(4H, m), 2.72(1H, dd, J=2, 14 Hz), 2.93(1H,d, J=14 Hz), 3.29(1H, s), 5.47(1H, s)

²⁴ ₅₈₉=+58.3 (c=1.02, MeOH) (literature;

²⁰ ₅₈₉=+54.5 (c=0.99, MeOH); Tetrahedron: Asymmetry, 6 (6), 1393, 1995)

Production Example 23 4-Ethynyl-1-azaadamantan-4-ol

[0547] To a solution of 0.2 ml of trimethylsilylacetylene in 2 ml oftetrahydrofuran was added dropwise 0.64 ml of a 1.56 mol hexane solutionof n-butyllithium in a dry ice-acetone bath. After stirring for 30minutes, a solution of 50 mg of 1-azaadamantane-4-one in 1 ml oftetrahydrofuran was added dropwise to the mixture. After furtherstirring for 30 minutes, 1 ml of methanol was added to the mixture andthe temperature was elevated to room temperature. The solvent wasremoved and water was added to the resulting solid. Crystals thatremained were collected by filtration, to give 17 mg of the titlecompound.

[0548]¹H-NMR(CDCl₃) δppm=1.52-2.06(5H, m), 2.26-2.38(2H, m),2.58-2.61(1H, m), 2.91-3.58(6H, m)

Production Example 242-Benzyl-3-iodo-6-(3,3-ethylenedioxypyrrolidin-1-yl)pyridine a)2-Bromo-6-(3,3-ethylenedioxypyrrolidin-1-yl)pyridine

[0549] A mixture of 5.7 g of 2,6-dibromopyridine, 2.5 g of3-hydroxypyrrolidine, 3.6 ml of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU)and 20 ml of tetrahydrofuran was heated under stirring under nitrogenatmosphere in an oil bath at 70° C. for 11 hours. The reaction mixturewas separated with ethyl acetate-water. The organic layer was washedwith water and brine, dried over anhydrous magnesium sulfate, and thenconcentrated. The residue was subjected to silicagel columnchromatography with 10-30% ethyl acetate/hexane, to give 5.9 g of2-bromo-6-(3-hydroxypyrrolidin-1-yl)pyridine.

[0550] Then, to a solution of 2.8 ml of oxalyl chloride in 100 ml ofdichloromethane were added dropwise 4.6 ml of dimethyl sulfoxide in adry ice-acetone bath while stirring, a solution of 5.9 g of the2-bromo-6-(3-hydroxypyrrolidin-1-yl)pyridine in 50 ml of dichloromethaneand finally 17 ml of triethylamine, and the temperature was returned toroom temperature over 1 hour. The reaction mixture was washed with waterand brine, dried over anhydrous magnesium sulfate and concentrated. Tothe residue were added 50 ml of toluene, 7 ml of ethylene glycol and acatalytic amount of p-toluenesulfonic acid monohydrate, followed byheating under reflux for 3 hours while removing water. After cooling, itwas washed with a saturated aqueous sodium hydrogen carbonate solutionand brine, dried over anhydrous magnesium sulfate and concentrated. Theresidue was subjected to silica gel column chromatography with 5-7%ethyl acetate/hexane, to give 6.3 g of the title compound.

[0551]¹H-NMR(CDCl₃) δppm=2.30(2H, t, J=7 Hz), 3.54(2H, s), 3.58(2H, t,J=7 Hz), 3.96-4.04(4H, m), 6.22(1H, d, J=8 Hz), 6.70(1H, d, J=8 Hz),7.24(1H, t, J=8 Hz)

b) 2-Benzyl-6-(3,3-ethylenedioxypyrrolidin-1-yl)pyridine

[0552] A mixture of 6.3 g of2-bromo-6-(3,3-ethylenedioxypyrrolidin-1-yl)pyridine, 240 mg of1,3-bis(diphenylphosphino)propanenickel (II) chloride and 20 ml oftetrahydrofuran was stirred in advance under nitrogen atmosphere in anice bath. To this was added dropwise a diethyl ether solution of benzylmagnesium bromide prepared from 3.4 ml of benzyl bromide, 0.8 g ofmagnesium and 15 ml of diethyl ether, followed by stirring as it was atroom temperature for overnight. The reaction mixture was partitionedbetween a saturated aqueous ammonium chloride solution and ethylacetate. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate and then concentrated. The residue was subjected tosilica gel column chromatography with 5-10% ethyl acetate/hexane, togive 6.6 g of the title compound.

[0553]¹H-NMR(CDCl₃) δppm=2.19(2H, t, J=7 Hz), 3.57(2H, s), 3.59(2H, t,J=7 Hz), 3.97 (2H, s), 4.01 (4H, s), 6.14 (1H, d, J=8 Hz), 6.34 (1H, d,J=7 Hz), 7.16-7.35(6H, m)

c) 2-Benzyl-3-iodo-6-(3,3-ethylenedioxypyrrolidin-1-yl)pyridine

[0554] A mixture of 6.6 g of2-benzyl-6-(3,3-ethylenedioxypyrrolidin-1-yl)pyridine and 60 ml ofN,N-dimethylformamide was stirred in advance in an ice bath. 5.5 g ofN-iodosuccinimide was added thereto and the resultant mixture wasstirred as it was at room temperature overnight. To the reaction mixturewas added 10 ml of a 1 M aqueous solution of sodium thiosulfate and thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and then concentrated. The residue was subjected to silica gelcolumn chromatography with 5-10% ethyl acetate/hexane, to give 6.7 g ofthe title compound.

[0555]¹H-NMR(CDCl₃) δppm=2.17(2H, t, J=7 Hz), 3.50(2H, s), 3.54(2H, t,J=7 Hz), 4.00(4H, s), 4.18(2H, s), 5.95(1H, d, J=8 Hz), 7.18(1H, t, J=7Hz), 7.26(2H, t, J=7 Hz), 7.37(2H, d, J=7 Hz), 7.68(1H, d, J=8 Hz)

Production Example 25 2-Benzyl-3-iodo-6-(4-methoxypiperidino)pyridine

[0556] The title compound was synthesized in the same manner as inProduction Example 1-e except that (3R,4R)-3,4-dihydroxypyrrolidineacetate was replaced by 4-piperidinol.

[0557] H-NMR(CDCl₃) δppm=1.50-1.61(2H, m), 1.87-1.95(2H, m),3.12-3.20(2H, m), 3.37(3H, s), 3.37-3.44(1H, m), 3.88-3.96(2H, m), 4.18(2H, s), 6.28 (1H, d, J=9 Hz), 7.18 (1H, t, J=8 Hz), 7.27 (2H, t, J=8Hz), 7.35(2H, d, J=8 Hz), 7.69(1H, d, J=9 Hz)

Production Example 262-Benzyl-3-iodo-6-[(3R,4R)-dimethoxypyrrolidin-1-yl]pyridine

[0558] The entitled compound was synthesized in the same manner as inProduction Example 1-f except that 2 equivalents each of sodium hydride,oily (60%) and methyl iodide were used.

[0559]¹H-NMR (CDCl₃) δppm=3.40(6H, s), 3.48-3.62(4H, m), 3.91-3.93(2H,m), 4.18(2H, s), 5.98(1H, d, J=8 Hz), 7.18(1H, t, J=7 Hz), 7.26(2H, t,J=7 Hz), 7.37(2H, d, J=7 Hz), 7.67(1H, d, J=8 Hz)

Example 13-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynyl-3-piperidinol

[0560] A mixture of 450 mg of2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1yl]-pyridine(Production Example 1), 272 mg of1-tert-butoxycarbonyl-3-ethynyl-3-piperidinol (Production Example 15),63.6 mg of tetrakis(triphenylphosphine)palladium (0), 41.9 mg of copper(I) iodide, 460 μl of triethylamine, 5 ml of methanol and 1 ml ofN,N-dimethyl formamide was heated under reflux under nitrogen atmospherefor 3 hours. After standing to cool, water, ethyl acetate, an aqueousammonia chloride solution were added to the reaction mixture, and theorganic layer was washed with water and brine, dried over anhydrousmagnesium sulfate and then the solvent was removed. To the residue wereadded 2 ml of trifluoroacetic acid and 2 ml of dichloromethane, followedby stirring at room temperature for 1 hour. The reaction mixture wasneutralized with an aqueous sodium hydrogen carbonate solution and anorganic layer was separated by adding ethyl acetate. The organic layerwas washed with brine, dried over anhydrous magnesium sulfate and thesolvent was removed. The residue was purified by NH-silica gel columnchromatography with 5% methanol/ethyl acetate, to give 387 mg of theentitled compound.

[0561]¹H-NMR(CDCl₃) δppm=1.52-1.56(1H, m), 1.67-1.75(1H, m),1.86-1.95(2H, m), 2.69-2.74(2H, m), 2.83-2.86(1H, m), 2.92-2.95(1H, m),3.41(3H, s), 3.46-3.55(2H, m), 3.66-3.74(2H, m), 3.84-3.86(1H, m),4.15(2H, s), 4.37-4.40(1H, m), 6.10-6.12(1H, m), 7.14-7.18(1H, m),7.23-7.26(2H, m), 7.32-7.35(2H, m), 7.40-7.42(1H, m)

Example 23-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl[-3-pyridyl]ethynyl-1-methyl-3-piperidinol

[0562] To a mixture of 94.0 mg of3-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynyl-3-piperidinol(Example 1), 34.6 μl of an aqueous solution of 37% formaldehyde and 1.5ml of dichloromethane was added 73.4 mg of sodium triacetoxyborohydrideunder ice-cooling, followed by stirring at room temperature for 30minutes. The organic layer was separated by adding water and ethylacetate to the reaction mixture, and then it was washed with an aqueoussodium hydrogen carbonate solution and brine, dried over anhydrousmagnesium sulfate, and the solvent was removed. The residue was purifiedby NH-silica gel column chromatography with 5% methanol/ethyl acetate,to give 79.0 mg of the title compound.

[0563]¹H-NMR(CDCl₃) δppm=1.62-1.71(2H, m), 1.82-2.08(3H, m), 2.30(3H,s), 2.33-2.36(1H, m), 2.62-2.77(2H, m), 3.41(3H, s), 3.46-3.55(2H, m),3.67-3.74(2H, m), 3.84-3.87(1H, m), 4.15(2H, s), 4.39-4.40(1H, m),6.12(1H, d, J=9 Hz), 7.14-7.27(3H, m), 7.38-7.44(3H, m)

Example 34-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]-1-methyl-4-piperidinol

[0564] To a mixture of 500 mg of2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine(Production Example 1) and 10 ml of diethyl ether was added dropwise1.99 ml of a 2.45 M hexane solution of n-butyllithium at −78° C. Afterstirring at the same temperature for 30 minutes, a solution of 552 mg of1-methyl-4-piperidone in 3 ml of diethyl ether was added dropwisethereto. After stirring at the same temperature for 30 minutes, thetemperature was elevated to room temperature. The organic layer wasseparated by adding water and ethyl acetate to the reaction mixture, andthen it was washed with water and brine, dried over anhydrous magnesiumsulfate and the solvent was removed. The residue was purified byNH-silica gel column chromatography with 5% methanol/ethyl acetate, togive 125 mg of the title compound.

[0565]¹H-NMR(CDCl₃) δppm=1.86-1.89(2H, m), 2.04-2.09(2H, m), 2.31(3H,s), 2.44-2.50(2H, m), 2.67-2.70(2H, m), 3.39(3H, s), 3.42-3.50(2H, m),3.64-3.72(2H, m), 3.83-3.84(1H, m), 4.34-4.36(1H, m), 4.41(2H, s),6.16(1H, d, J=9 Hz), 7.13-7.15(1H, m), 7.21-7.24(2H, m), 7.32-7.33(2H,m), 7.43-7.45(1H, m)

Example 44-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]-1-methyl-1,2,3,6-tetrahydropyridine

[0566] A mixture of 63.0 mg of4-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]-1-methyl-4-piperidinol(Example 3) and 1.5 ml of 1 M acetic acid solution of hydrogen chloridewas stirred at 70° C. for 9 hours. The reaction mixture was neutralizedwith an aqueous sodium hydrogen carbonate solution and extracted withethyl acetate. The organic layer was washed with water and brine, driedover anhydrous magnesium sulfate, and the solvent was removed. To theresidue were added 50 mg of potassium carbonate and 1 ml of methanol,followed by stirring at room temperature for 1 hour. NH-silica gel wasadded to the reaction mixture and the solvent was removed. It waspurified by NH-silica gel column chromatography with 5% methanol/ethylacetate, to give 10.2 mg of the title compound.

[0567]¹H-NMR(CDCl₃) δppm=2.26-2.27(2H, m), 2.39(3H, s), 2.58(2H, t, J=6Hz), 3.03(2H, d, J=3 Hz), 3.40(3H, s), 3.44-3.52(2H, m), 3.67-3.75(2H,m), 3.84-3.87(1H, m), 4.01(2H, s), 4.36-4.38(1H, m), 5.42-5.43(1H, m),6.18(1H, d, J=8 Hz), 7.13-7.30(6H, m)

Example 53-[3-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl)-3-pyridyl]propyloxy]pyrrolidine

[0568] A mixture of 742 mg of2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine(Production Example 1), 389 mg of 1-benzyl-3-(2-propynyloxy)pyrrolidine(Production Example 16), 62.7 mg oftetrakis(triphenylphosphine)palladium (0), 51.7 mg of copper (I) iodide,757 μl of triethylamine, 4 ml of methanol and 4 ml ofN,N-dimethylformamide was stirred under nitrogen atmosphere at 75° C.for 2 hours. After standing to cool, water, ethyl acetate and aqueousammonia were added to the reaction mixture. The organic layer wasseparated, washed with water and brine, dried over anhydrous magnesiumsulfate, filtered through NH-silica gel and the solvent was removed.After 10 ml of methanol, 1 ml of acetic acid and 50 mg of 10% palladiumcarbon were added to the residue and hydrogen substitution wasperformed, the mixture was stirred at room temperature overnight. Afterthe reaction mixture was nitrogen-purged, it was filtered throughCelite. The solvent was removed, and then the residue was purified bysilica gel column chromatography with ethyl acetate/methanol/aqueousammonia (100/5/2), to give 465 mg of the title compound.

[0569]¹H-NMR(CDCl₃) δppm=1.65-1.72(2H, m), 1.76-1.79(1H, m),2.04-2.09(1H, m), 2.45-2.57(4H, m), 2.61-2.65(1H, m), 2.76-2.80(1H, m),3.23-3.29(2H, m), 3.42(3H, s), 3.45-3.51(2H, m), 3.57-3.77(4H, m),3.85-3.88(1H, m), 3.94-3.97(1H, m), 4.03(2H, s), 4.37-4.40(1H, m),6.18(1H, d, J=8 Hz), 7.13-7.15(1H, m), 7.20-7.34(5H, m)

Example 61-[2-Benzyl-6-[3R,4S)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynylcyclohexylamine

[0570] To a mixture of 200 mg of2-benzyl-3-iodo-6-[(3R,4S)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine(Production Example 2), 100 mg of 1-ethynylcyclohexylamine, 15 mg oftetrakis(triphenylphosphine)palladium (0), 5 mg of copper (I) iodide and0.3 ml of triethylamine was added 1 ml of N,N-dimethylformamide,followed by heating under stirring under nitrogen atmosphere in an oilbath at 80° C. for 3 hours. After standing to cool, aqueous ammonia wasadded to the reaction mixture, which then was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andthe solvent was removed. The residue was purified by NH-silica gelcolumn chromatography with ethyl acetate, to give 155 mg of the titlecompound.

[0571]¹H-NMR(CDCl₃) δppm=1.10-1.95(10H, m), 3.42-3.55(5H, m),3.60-3.72(2H, m), 3.94(1H, q, J=6 Hz), 4.17(2H, d, J=3 Hz),4.38-4.43(1H, m), 6.12(1H, d, J=9 Hz), 7.15(1H, t, J=7 Hz),7.22-7.28(2H, m), 7.35(2H, d, J=7 Hz), 7.42(1H, d, J=9 Hz)

Example 71-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynylcyclohexylamine

[0572] This was synthesized in the same manner as in Example 6 exceptthat2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine(Production Example 1) was used.

[0573]¹H-NMR(CDCl₃) δppm=1.10-1.91(10H, m), 3.41(3H, s), 3.45-3.55(2H,m), 3.66-3.75(2H, m), 3.83-3.88(1H, m), 4.17(2H, s), 4.37-4.42(1H, m),6.14(1H, d, J=9 Hz), 7.15(1H, t, J=7 Hz), 7.21-7.28(2H, m), 7.35(2H, d,J=7 Hz), 7.41(1H, d, J=9 Hz)

Example 81-[2-Benzyl-6-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinon-1-yl]-3-pyridyl]ethynylcyclohexylamine

[0574] This was synthesized in the same manner as in Example 6 exceptthat 2-benzyl-6-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinon-1-yl]-3-pyridyltrifluoromethanesulfonate (Production Example 7-A) was used.

[0575]¹H-NMR(CDCl₃) δppm=1.10-1.95(10H, m), 3.47(3H, s), 3.70(3H, s),3.83(1H, dd, J=4, 13 Hz), 4.07(1H, d, J=5 Hz), 4.12-4.18(1H, m),4.23(1H, dd, J=2, 13 Hz), 4.26(2H, d, J=2 Hz), 7.15-7.34(5H, m),7.67(1H, d, J=9 Hz), 8.21(1H, d, J=9 Hz)

Example 91-[2-Benzyl-6-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinon-1-yl]-3-pyridyl]ethynylcyclohexylamine

[0576] This was synthesized in the same manner as in Example 6 exceptthat2-benzyl-6-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinon-1-yl]-3-pyridyltrifluoromethanesulfonate (Production Example 7-B) was used.

[0577]¹H-NMR(CDC1₃) δppm=1.10-1.95(10H, m), 3.74(3H, s), 3.89(1H, dd,J=4, 13 Hz), 4.06 (1H, d, J=4 Hz), 4.18 (1H, d, J=13 Hz), 4.25 (2H, s),4.54 (1H, t, J=4 Hz), 7.15-7.35 (5H, m), 7.68 (1H, d, J=9 Hz) 8.20(1H,d, J=9 Hz)

Example 101-[1-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynylcyclohexyl]piperidine

[0578] This was synthesized in the same manner as in Example 6 exceptthat2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine(Production Example 1) and 1-(1-ethynylcyclohexyl)piperidine (ProductionExample 18) were used.

[0579]¹H-NMR(DMSO-d₆) δppm=1.18-1.64 (14H, m), 1.86-1.93 (2H, m),2.46-2.56(4H, m), 3.24-3.52(7H, m), 3.71-3.75(1H, m), 4.08(2H, s),4.17-4.21(1H, m), 5.22(1H, brs), 6.26(1H, d, J=8.4 Hz), 7.11-7.29(5H,m), 7.42(1H, d, J=8.4 Hz)

Example 111-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynyl-N-methylcyclohexylamine

[0580] This was synthesized in the same manner as in Example 6 exceptthat2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine(Production Example 1) and 1-ethynyl-N-methylcyclohexylamine (ProductionExample 19) were used.

[0581]¹H-NMR(DMSO-d₆) δppm=1.05-1.82(10H, m), 2.30(3H, s), 3.24-3.52(7H,m), 3.72(1H, brs), 4.07(2H, s), 4.19(1H, brs), 5.23(1H, brs), 6.26(1H,d, J=8.4 Hz), 7.12-7.31(5H, m), 7.40(1H, d, J=8.4 Hz)

Example 122-[[1-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynylcyclohexyl]amino]ethanol

[0582] This was synthesized in the same manner as in Example 6 exceptthat2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine(Production Example 1) and 2-[(1-ethynylcyclohexyl)amino]ethanol(Production Example 20) were used.

[0583]¹H-NMR(DMSO-d₆) δppm=1.11-1.86(10H, m), 2.73(2H, t, J=6 Hz),3.27(3H, s), 3.41-3.51(4H, m), 3.73(1H, brs), 4.06(2H, s), 4.19(1H, brs),4.49(2H, t, J=6 Hz), 5.23(1H, d, J=3 Hz), 6.26(1H, d, J=8.4 Hz),7.13-7.31(5H, m), 7.40(1H, d, J=8.4 Hz)

Example 133-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]-1,1-diethyl-2-propynylamine

[0584] This was synthesized in the same manner as in Example 6 exceptthat2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine(Production Example 1) and 1,1-diethyl-2-propynylamine were used.

[0585]¹H-NMR(CDCl₃) δppm=1.04(6H, t, J=8 Hz),1.50-1.75(4H, m), 3.40(3H,s), 3.45-3.54(2H, m), 3.65-3.74(2H, m), 3.82-3.86(1H, m), 4.16(2H, s),4.35-4.40(1H, m), 6.12(1H, d, J=9 Hz), 7.15(1H, t, J=8 Hz), 7.24(2H, t,J=8 Hz), 7.34(2H, d, J=8 Hz), 7.40(1H, d, J=9 Hz)

Example 142-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynylbicyclo[2.2.1]heptan-2-ol

[0586] This was synthesized in the same manner as in Example 6 exceptthat2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine(Production Example 1) and 2-ethynylbicyclo[2.2.1)heptan-2-ol(Production Example 21) were used.

[0587]¹H-NMR(DMSO-d₆) δppm=1.15-1.32(4H, m), 1.41-1.52(1H, m), 1.67 (1H,d, J=9 Hz), 1.88-2.04 (2H, m), 2.15-2.18(1H, m), 2.30 (1H, d, J=3 Hz),3.27 (3H, s), 3.28-3.52(4H, m), 3.73(1H, brs), 4.03(2H, s), 4.19(1H,brs), 5.24(1H, brs), 5.42(1H, s), 6.26(1H, d, J=8.4 Hz), 7.14(1H, t, J=7Hz), 7.23(2H, t, J=7 Hz), 7.32(2H, d, J=7 Hz), 7.38(1H, d, J=8.4 Hz)

Example 15(3R)-3-[2-Benzyl-4-(2-pyrrolidinon-1-yl)phenyl]ethynyl-3-quinuclidinol

[0588] To a mixture of 200 mg of 2-benzyl-4-[2-pyrrolidinon-1-yl]phenyltrifluoromethanesulfonate (Production Example 5), 80 mg of(3R)-3-ethynyl-3-quinuclidinol (Production Example 22), 30 mg oftetrakis(triphenylphosphine)palladium (0), 5 mg of copper (I) iodide and0.2 ml of triethylamine was added 1 ml of N,N-dimethylformamide,followed by heating under stirring under nitrogen atmosphere in an oilbath at 80° C. for 3 hours. After standing to cool, aqueous ammonia wasadded to the reaction mixture, which then was extracted with ethylacetate. The organic layer was washed with brine and dried overanhydrous sodium sulfate. The solvent was removed and the residue waspurified by NH-silica gel column chromatography with ethyl acetate, togive 66 mg of the title compound.

[0589]¹H-NMR(CDCl₃) δppm=1.32-1.41(1H, m), 1.50-1.60(1H, m),1.77-1.87(1H, m), 1.95-2.05(2H, m), 2.09-2.18(2H, m), 2.59(2H, t, J=8Hz), 2.62-2.91(4H, m), 2.98(1H, dd, J=2, 14 Hz), 3.18(1H, dd, J=2, 14Hz), 3.80(2H, t, J=7 Hz), 4.15(2H, s), 7.14-7.21(3H, m), 7.24-7.29(2H,m), 7.42(1H, d, J=8 Hz), 7.46(1H, d, J=2 Hz), 7.52(1H, dd, J=2, 8 Hz)

Example 16(3R)-3-[2-Benzyl-4-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinon-1-yl)phenyl]ethynyl-3-quinuclidinol

[0590] This was synthesized in the same manner as in Example 15 exceptthat 2-benzyl-4-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinon-1-yl]phenyltrifluoromethanesulfonate (Production Example 9) was used.

[0591]¹H-NMR(CDCl₃) δppm=1.35-1.90(3H, m), 1.96-2.07(2H, m),2.65-2.93(4H, m), 3.00(1H, dd, J=2, 14 Hz), 3.19(1H, dd, J=2, 14 Hz),3.71-3.79(4H, m), 3.82(1H, dd, J=4, 11 Hz), 4.02(1H, d, J=5 Hz),4.15(2H, s), 4.52-4.58(1H, m), 7.14-7.22(3H, m), 7.24-7.30(2H, m),7.44(1H, d, J=8 Hz), 7.47(1H, d, J=2 Hz), 7.54(1H, dd, J=2, 8 Hz)

Example 17(3R)-3-[2-Benzyl-4-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinon-1yl]phenyl]ethynyl-3-quinuclidinol

[0592] This was synthesized in the same manner as in Example 15 exceptthat 2-benzyl-4-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinon-1-yl]phenyltrifluoromethanesulfonate (Production Example 8) was used.

[0593]¹H-NMR(CDCl₃) δppm=1.34-1.89(3H, m), 1.95-2.06(2H, m),2.64-2.92(4H, m), 2.99(1H, dd, J=2, 14 Hz), 3.18(1H, dd, J=2, 14 Hz),3.48 (3H, s), 3.69 (3H, s), 3.77 (2H, d, J=4 Hz), 4.02 (1H, d, J=5 Hz),4.12-4.18(3H, m), 7.14-7.22(3H, m), 7.24-7.30(2H, m), 7.43(1H, d, J=8Hz), 7.46(1H, d, J=2 Hz), 7.53(1H, dd, J=2, 8 Hz)

Example 18(3R)-3-[2-Benzyl-4-[(3R,4S)-3,4-dimethoxypyrrolidin-1-yl)phenyl]ethynyl-3-quinuclidinol

[0594] Under ice-cooling, 227 mg of N-iodosuccinimide was added to amixture of 250 mg of (3R,4S)-1-(3-benzylphenyl)-3,4-dimethoxypyrrolidine(Production Example 11) and 3 ml of N,N-dimethylformamide, followed bystirring at the same temperature for 2 hours. 0.5 ml of a 1 M aqueoussolution of sodium thiosulfate was added to the reaction mixture, andthen the mixture was extracted with ethyl acetate/water. The organiclayer was washed with water and brine, dried over anhydrous magnesiumsulfate and then evaporated. The residue was subjected to silica gelcolumn chromatography with 10% ethyl acetate/hexane, to give 340 mg of(3R,4S)-1-(3-benzyl-4-iodophenyl-3,4-dimethoxypyrrolidine.

[0595] Then, a mixture of 340 mg of(3R,4S)-1-(3-benzyl-4-iodophenyl-3,4-dimethoxypyrrolidine, 134 mg of(3R)-3-ethynyl-3-quinuclidinol (Production Example 22), 9 mg oftetrakis(triphenylphosphine)palladium (0), 8 mg of copper (I) iodide,0.22 ml of triethylamine and 0.8 ml of methanol was stirred undernitrogen atmosphere at room temperature for 4 hours. After ethyl acetateand methanol were added to the reaction mixture for dissolution,NH-silica gel was added thereto and the reaction mixture was evaporated.The residue was subjected to column chromatography using NH-silica gelwith 50% ethyl acetate/hexane and 0-2.5% methanol/ethyl acetate, to give220 mg of the title compound.

[0596]¹H-NMR(CDCl₃) δppm=1.31-1.42(1H, m), 1.46-1.57(1H, m),1.77-1.88(1H, m), 1.93-2.06(2H, m), 2.62-2.91(4H, m), 2.96(1H, dd, J=2,14 Hz), 3.16(1H, dd, J=2, 14 Hz), 3.37(2H, dd, J=4, 10 Hz),3.42-3.51(8H, m), 3.96-4.03(2H, m), 4.09(2H, s), 6.30(1H, d, J=2 Hz),6.35(1H, dd, J=2, 8 Hz), 7.14-7.33(6H, m)

Example 19(3R)-3-[2-Benzyl-4-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]phenyl]ethynyl-3-quinuclidinol

[0597] This was synthesized in the same manner as in Example 18 exceptthat (3R,4S)-1-(3-benzylphenyl)-3,4-dihydroxypyrrolidine (ProductionExample 10) was used.

[0598]¹H-NMR(DMSO-d₆) δppm=1.20-1.30(1H, m), 1.38-1.50(1H, m),1.65-1.76(1H, m), 1.82-1.92(2H, m), 2.44-2.70(4H, m), 2.77(1H, d, J=14Hz), 2.94(1H, d, J=14 Hz), 3.05(2H, dd, J=4, 10 Hz), 3.36(2H, dd, J=6,10 Hz), 4.01(2H, s), 4.07-4.15(2H, m), 4.91(2H, d, J=5 Hz), 5.45(1H, s),6.31(1H, dd, J=2, 8 Hz), 6.35(1H, d, J=2 Hz), 7.12-7.28(6H, m)

Example 20(3R)-3-[2-Benzyl-4-[cis-3-hydroxy-4-methoxypyrrolidin-1-yl]phenyl]ethynyl-3-quinuclidinol

[0599] This was synthesized in the same manner as in Example 18 exceptthat 1-(3-benzylphenyl)-cis-3-hydroxy-4-methoxypyrrolidine (ProductionExample 12) was used.

[0600]¹H-NMR(CDCl₃) δppm=1.32-2.06(5H, m), 2.60-2.91(4H, m), 2.97(1H, d,J=14 Hz), 3.17(1H, dd, J=2, 14 Hz), 3.25-3.36(2H, m), 3.45-3.54(5H, m),3.95(1H, q, J=5 Hz), 4.09(2H, s), 4.41(1H, br.s), 6.29(1H, d, J=3 Hz),6.34(1H, dd, J=3, 8 Hz), 7.14-7.33(6H, m)

Example 21(3R)-3-[2-Benzyl-4-[trans-3-hydroxy-4-methoxypyrrolidin-1-yl]phenyl]ethynyl-3-quinuclidinol

[0601] To a mixture of 460 mg of1-(3-bromophenyl)-trans-3-hydroxy-4-methoxypyrrolidine (ProductionExample 13), 46 mg of 1,3-bis(diphenylphosphino)propanenickel (II)chloride and 5 ml of tetrahydrofuran was added dropwise 2.5 ml of a 2.0M tetrahydrofuran solution of benzyl magnesium chloride while stirringat room temperature, followed by stirring for 3 hours. The reactionmixture was separated with a saturated aqueous ammonium chloridesolution-ethyl acetate, and the organic layer was washed with water andbrine, dried over anhydrous magnesium sulfate and then evaporated. Theresidue was subjected to silica gel column chromatography with 10-30%ethyl acetate/hexane. Subsequently, the resulting compound was subjectedto the same operations as those in Example 18 to synthesize the titlecompound.

[0602]¹H-NMR(CDCl₃) δppm=1.31-1.88(3H, m), 1.93-2.07(2H, m),2.62-2.91(4H, m), 2.97(1H, dd, J=2, 14 Hz), 3.16(1H, dd, J=2, 14 Hz),3.21-3.29(2H, m), 3.41(3H, s), 3.54-3.63(2H, m), 3.83-3.88(1H, m),4.09(2H, s), 4.37-4.42(1H, m), 6.32(1H, d, J=2 Hz), 6.37(1H, dd, J=2, 8Hz), 7.14-7.32(6H, m)

Example 223-[4-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]phenyl]-3-quinuclidinol

[0603] To a mixture of 280 mg of2-(4-bromophenyl)-6-methyl-1,3,6,2-dioxyazaborocane (Production Example14) and 10 ml of tetrahydrofuran was added dropwise 2 ml of a 1 Mcyclohexane-hexane solution of sec-butyllithium under nitrogenatmosphere while cooling in a liquid nitrogen-tetrahydrofuran bath at−90° C., followed by stirring as it was for 40 minutes. Then, a solutionof 130 mg of 3-quinuclidinone in 1 ml of tetrahydrofuran was added tothe mixture, the liquid nitrogen-tetrahydrofuran bath was removed andthe mixture was stirred at room temperature for 30 minutes. 1 ml of anaqueous ammonium chloride solution was added to the reaction mixture,followed by evaporating. To the residue were added 5 ml of methanol, 2ml of a 5 Maqueous solution of potassium carbonate, 220 mg of2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridinehydrochloride and 5 ml of diethoxymethane, followed by heating understirring under nitrogen atmosphere in an oil bath at 60° C. for 3 hours.The reaction mixture was extracted with ethyl acetate-water, and theorganic layer was washed with water and brine, dried over anhydrousmagnesium sulfate and then evaporated. The residue was subjected tocolumn chromatography using NH-silica gel with 50% ethyl acetate-hexaneand 0-5% methanol-ethyl acetate, to give 60 mg of the title compound.

[0604]¹H-NMR(DMSO-d₆) δppm=1.22-1.46(3H, m), 1.92-1.97(1H, m),2.08-2.18(1H, m), 2.58-2.92(6H, m), 3.30(3H, s), 3.31-3.57(4H, m),3.73-3.78(1H, m), 3.92(2H, s), 4.19-4.13(1H, m), 5.13(1H, s), 5.23(1H,d, J=4 Hz), 6.37(1H, d, J=8 Hz), 7.05-7.23(7H, m), 7.36(1H, d, J=8 Hz),7.53(2H, d, J=8 Hz)

Example 23(E)-3-[2-[2-Benzyl-6-(2-pyrrolidinon-1-yl)pyridin-3-yloxy]-1-fluoroethynylidene]quinuclidine

[0605] 70 mg of 2-benzyl-3-hydroxy-6-(2-pyrrolidinon-1-yl)pyridine(Production Example 6), 50 mg ofborane-[(E)-3-(2-chloro-1-fluoroethynylidene)quinuclidine] complex(synthesized by the method described in WO96/26938 A) and 70 mg ofanhydrous potassium carbonate were suspended in 1 ml ofN,N-dimethylformamide, followed by stirring at room temperatureovernight. Subsequently, water was slowly added to the mixture untilprecipitates were formed, and the resulting solid was collected byfiltration. The solid was dissolved in 2 ml of acetone and 0.3 ml of 5 Nhydrochloric acid was added dropwise thereto in an ice bath. After thetemperature was returned to room temperature and stirring was continuedfor 1 hour, 10 ml of 1 N hydrochloric acid was added to the reactionmixture and the aqueous layer was washed with t-butyl methyl ether.Subsequently, anhydrous potassium carbonate was added to the aqueouslayer to make it weakly basic, and it was extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous magnesiumsulfate and the solvent was evaporated, to give 70 mg of the titlecompound.

[0606]¹H-NMR(CDCl₃) δppm=1.56-1.73(4H,m), 2.05-2.14(2H,m), 2.63(2H, t,J=8 Hz), 2.75-2.96(4H, m), 3.00(1H, t, J=3 Hz), 3.34(2H, d, J=3 Hz),4.07(2H, t, J=7 Hz), 4.11(2H, s), 4.42(2H, d, J=20 Hz) 7.14-7.32(6H, m),8.17(1H, d, J=9 Hz)

Example 241-[2-Benzyl-6-(3,3-ethylenedioxypyrrolidin-1-yl]-3-pyridyl]ethynylcyclohexylamine

[0607] This was synthesized in the same manner as in Example 6 exceptthat 2-benzyl-3-iodo-6-(3,3-ethylenedioxypyrrolidin-1-yl)pyridine(Production Example 24) was used.

[0608]¹H-NMR(CDCl₃) δppm=1.09-1.91(10H, m), 2.17(2H, t, J=7 Hz),3.54(2H, s), 3.59(2H, t, J=7 Hz), 4.01(4H, s), 4.17(2H, s), 6.12(1H, d,J=9 Hz), 7.12-7.37(5H, m), 7.41(1H, d, J=9 Hz)

Example 251-[2-Benzyl-6-(4-methoxypiperidino)-3-pyridyl]ethynylcyclohexylamine

[0609] This was synthesized in the same manner as in Example 6 exceptthat 2-benzyl-3-iodo-6-(4-methoxypiperidino)pyridine (Production Example25) was used.

[0610]¹H-NMR(CDCl₃) δppm=1.09-1.96 (14H, m), 3.16-3.23 (2H, m),3.37 (3H,s), 3.37-3.46(1H, m), 3.96-4.03(2H, m), 4.17(2H, s), 6.44(1H, d, J=9Hz), 7.16(1H, t, J=7 Hz), 7.24(2H, t, J=7 Hz), 7.33(2H, d, J=7 Hz),7.42(1H, d ,J=9 Hz)

Example 264-[2-Benzyl-6-[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]-3-pyridyl]ethynyl-exo-1-azaadamantan-4-ol(A) and4-[2-benzyl-6-[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]-3-pyridyl]ethynyl-endo-1-azaadamantan-4-ol(B)

[0611] These compounds were synthesized in the same manner as in Example15 except that2-benzyl-3-iodo-6-[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]pyridine(Production Example 26) and 4-ethynyl-1-azaadamantan-4-ol (ProductionExample 23) were used. The compounds (A) and (B) were separated andpurified by NH-silica gel column chromatography with ethyl acetate and10% methanol/ethyl acetate as an elution solvent.

[0612] Compound A: ¹H-NMR (CDCl₃) δppm=1.55(1H, brs), 1.79(2H, d, J=12Hz), 1.85(2H, brs), 2.37(2H, d, J=12 Hz), 3.07(2H, brs), 3.16(2H, d,J=13 Hz), 3.37(2H, d, J=13 Hz), 3.41(6H, s), 3.53-3.67(4H, m),3.91-3.95(2H, m), 4.15(2H, s), 6.14(1H, d, J=9 Hz), 7.15(1H, t, J=8 Hz),7.24(2H, t, J=8 Hz), 7.30(2H, d, J=8 Hz), 7.40(1H, d, J=9 Hz)

[0613] Compound B: ¹H-NMR (CDCl₃) δppm=1.56-1.63(1H, m), 1.82(2H, brs),1.97(2H, d, J=13 Hz), 2.26 (2H, d, J=13 Hz), 2.97 (2H, d, J=13 Hz),3.09(2H, brs), 3.41(6H, s), 3.53-3.67(6H, m), 3.91-3.95(2H, m), 4.17(2H,s), 6.16(1H, d, J=8 Hz), 7.16(1H, t, J=7 Hz), 7.24(2H, t, J=7 Hz),7.31(2H, d, J=7 Hz), 7.40(1H, d, J=8 Hz) TABLE 3 Example 1 

Example 2 

Example 3 

Example 4 

Example 5 

Example 6 

Example 7 

Example 8 

Example 9 

Example 10

Example 11

Example 12

Example 13

Example 14

Example 15

Example 16

Example 17

Example 18

Example 19

Example 20

Example 21

Example 22

Example 23

Example 24

Example 25

Example 26(A)

Example 26(B)

1. A compound (I) represented by the formula:

(wherein R¹ represents an optionally substituted vinyl group or anaromatic ring which may be substituted; n is an integer of 0 to 2; X, Y,and Z are the same as or different from each other and each representsan optionally substituted carbon atom, or an optionally substitutednitrogen atom, sulfur atom or oxygen atom, and Y may represent a singlebond and when Y represents the single bond, the ring to which X, Y and Zbelong is a 5-membered; CyA represents a 5- to 14 membered non-aromaticcyclic amino group or non-aromatic cyclic amido group, each of which maybe substituted, and the non-aromatic cyclic amino group or thenon-aromatic cyclic amido group may contain an oxygen atom or a sulfuratom; W represents a chain expressed by (1) optionally substituted—CH₂—CH₂—, (2) optionally substituted —CH═CH—, (3) —C≡C—, (4) anoptionally substituted phenylene group, (5) a single bond, (6) —NH—CO—,(7) —CO—NH—, (8) —NH—CH₂—, (9) —CH₂—NH—, (10) —CH₂—CO—, (11) —CO—CH₂—,(12) —O—(CH₂)_(m)—, (13) —(CH₂)_(m)—O— (where m represents an integer of0 to 5), (14) —O—CH₂—CR²═, (15) —O—CH₂—CHR²— (where R² represents ahydrogen atom, a C₁₋₆ alkyl group, or a halogen atom), (16) —NH—S(O)₁—,(17) —S(O)₁—NH—, (18) —CH₂—S(O)₁— or (19) —S(O)₁—CH₂— (where 1represents 0, 1, or 2); and A represents a group having any of thefollowing structural formulae:

 (wherein R³ and R⁴ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring; R⁵ and R⁶ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring; R⁷ represents a hydrogen atom, an optionally substituted C₁₋₆alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or anoptionally substituted amino group; R⁸ represents a hydrogen atom, ahydroxyl group, an alkoxy group, a halogen atom or an optionallysubstituted amino group, B¹ represents an optionally substituted carbonatom, or an optionally substituted nitrogen atom, oxygen atom or sulfuratom; B² represents an optionally substituted carbon atom or nitrogenatom; a and b represent an integer of 0 to 4, provided that a+b is aninteger of 0 to 4, c represents 0 or 1; and

 represents a single bond or a double bond, provided that when c is 1 inwhich A is a quinuclidine having R⁸ represented by

 the case where R⁸ is a hydrogen atom or a hydroxyl group; Arl is anaromatic heterocycle; and W is one of (1) to (3), (6) to (11) and (16)to (19) are excluded)), a salt thereof or a hydrate of them.
 2. Thecompound according to claim 1, a salt thereof or a hydrate of them,wherein R¹ represents an optionally substituted vinyl group, a benzenering which may be substituted or a thiophene ring which may besubstituted; n is an integer of 0 to 2; Arl represents a benzene ring,pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, triazinering, thiazole ring, thiophene ring, pyrrole ring or furan ring, each ofwhich may be substituted with a lower alkyl group, a halogen atom or analkoxy group; CyA represents an azetidine ring, pyrrolidine ring,piperidine ring, piperazine ring, morpholine ring, 2-azetidinone ring,2-pyrrolidinone ring, 2-piperidinone ring, 2-piperazinone ring or3-morpholine ring, each of which may be substituted with one to threegroups which are the same as or different from each other selected from:(1) a lower alkyl group which may be substituted, (2) a lower alkenylgroup which may be substituted, (3) a lower alkynyl group which may besubstituted, (4) a lower alkoxy group which may be substituted, (5) anoxo group, (6) a nitrile group, (7) an alkylenedioxy group, (8) ahydroxyl group, (9) a halogen atom, (10) an amino group which may besubstituted, (11) an acylamino group, (12) a carbamoyl group which maybe substituted, (13) a carbamoyloxy group which may be substituted, (14)a carboxyl group, (15) an acyl group, (16) an acyloxy group, and (17) analkoxycarbonyloxy group; W represents a chain expressed by (1)optionally substituted —CH₂—CH₂—, (2) optionally substituted —CH═CH—,(3) —C≡C—, (4) an optionally substituted phenylene group, (5) a singlebond, (6) —NH—CO—, (7) —CO—NH—, (8) —NH—CH₂—, (9) —CH₂—NH—, (10)—CH₂—CO—, (11) —CO—CH₂—, (12) —O—(CH₂)_(m)—, (13) —(CH₂)_(m)—O— (where mrepresents an integer of 0 to 5), (14) —O—CH₂—CR² ═, (15) —O—CH₂—CHR—(where R² represents a hydrogen atom, a C₁₋₆ alkyl group, or a halogenatom), (16) —NH—S(O)₁—, (17) —S(O)₁—NH—, (18) —CH₂—S(O)₁— or (19)—S(O)₁—CH₂— (where 1 represents 0, 1, or 2); and A represents a grouphaving any of the following structural formulae:

 (wherein R³ and R⁴ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring; R⁵ and R⁶ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring; R⁷ represents a hydrogen atom, an optionally substituted C₁₋₆alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or anoptionally substituted amino group; R⁸ represents a hydrogen atom, ahydroxyl group, an alkoxy group, a halogen atom or an optionallysubstituted amino group, B¹ represents an optionally substituted carbonatom, or an optionally substituted nitrogen atom, oxygen atom or sulfuratom; B² represents an optionally substituted carbon atom or nitrogenatom; a and b represent an integer of 0 to 4, provided that a+b is aninteger of 0 to 4, c represents 0 or 1; and

 represents a single bond or a double bond, provided that when c is 1 inwhich A is a quinuclidine having R⁸ represented by

 the case where R⁸ is a hydrogen atom or a hydroxyl group; Arl is anaromatic heterocycle; and W is one of (1) to (3), (6) to (11) and (16)to (19) are excluded).
 3. The compound according to claim 1, a saltthereof or a hydrate of them, wherein Arl preferably represents abenzene ring, pyridine ring, pyrimidine ring or thiazole ring optionallysubstituted with a lower alkyl group, a halogen atom or an alkoxy group;R¹ represents an optionally substituted vinyl group, a benzene ringwhich may be substituted or a thiophene ring which may be substituted; nis an integer of 0 to 2; CyA represents an azetidine ring, pyrrolidinering, piperidine ring, piperazine ring, morpholine ring, 2-azetidinonering, 2-pyrrolidinone ring, 2-piperidinone ring, 2-piperazinone ring or3-morpholine ring, each of which may be substituted with one to threegroups which are the same as or different from each other selected from:(1) a lower alkyl group which may be substituted, (2) a lower alkenylgroup which may be substituted, (3) a lower alkynyl group which may besubstituted, (4) a lower alkoxy group which may be substituted, (5) anoxo group, (6) a nitrile group, (7) an alkylenedioxy group, (8) ahydroxyl group, (9) a halogen atom, (10) an amino group which may besubstituted, (11) an acylamino group, (12) a carbamoyl group which maybe substituted, (13) a carbamoyloxy group which may be substituted, (14)a carboxyl group, (15) an acyl group, (16) an acyloxy group, and (17) analkoxycarbonyloxy group; W represents a chain expressed by (1)optionally substituted —CH₂—CH₂—, (2) optionally substituted —CH═CH—,(3) —C═C—, (4) an optionally substituted phenylene group, (5) a singlebond, (6) —NH—CO—, (7) —CO—NH—, (8) —NH—CH₂—, (9) —CH₂—NH—, (10)—CH₂—CO—, (11) —CO—CH₂—, (12) —O—(CH₂)_(m)—, (13) —(CH₂)_(m)—O— (where mrepresents an integer of 0 to 5), (14) —O—CH₂—CR²═, (15) —O—CH₂—CHR²—(where R² represents a hydrogen atom, a C₁₋₆ alkyl group, or a halogenatom), (16) —NH—S(O)₁—, (17) —S(O)₁—NH—, (18) —CH₂—S(O)₁— or (19)—S(O)₁—CH₂— (where 1 represents 0, 1, or 2); and A represents a grouphaving any of the following structural formulae:

 (wherein R³ and R⁴ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring; R⁵ and R⁶ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring; R⁷ represents a hydrogen atom, an optionally substituted C₁₋₆alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or anoptionally substituted amino group; R⁸ represents a hydrogen atom, ahydroxyl group, an alkoxy group, a halogen atom or an optionallysubstituted amino group, B¹ represents an optionally substituted carbonatom, or an optionally substituted nitrogen atom, oxygen atom or sulfuratom; B² represents an optionally substituted carbon atom or nitrogenatom; a and b represent an integer of 0 to 4, provided that a+b is aninteger of 0 to 4, c represents 0 or 1; and

 represents a single bond or a double bond, provided that when c is 1 inwhich A is a quinuclidine having R⁸ represented by

 the case where R⁸ is a hydrogen atom or a hydroxyl group; Arl is anaromatic heterocycle; and W is one of (1) to (3), (6) to (11) and (16)to (19) are excluded).
 4. The compound according to claim 1, a saltthereof or a hydrate of them, wherein W preferably represents a chainexpressed by (1) optionally substituted —CH₂—CH₂—, (2) optionallysubstituted —CH═CH—, (3) —C≡C—, (4) an optionally substituted phenylenegroup, (5) a single bond, (13) —(CH₂)_(m)—O— (where m represents aninteger of 0 to 5), (14) —O—CH₂—CR²═, or (15) —O—CH₂—CHR²— (where R²represents a hydrogen atom, an alkyl group or a halogen atom); R¹represents an optionally substituted vinyl group, a benzene ring whichmay be substituted or a thiophene ring which may be substituted; n is aninteger of 0 to 2; Arl represents a benzene ring, pyridine ring,pyrimidine ring, pyrazine ring, pyridazine ring, triazine ring, thiazolering, thiophene ring, pyrrole ring or furan ring, each of which may besubstituted with a lower alkyl group, a halogen atom or an alkoxy group;CyA represents an azetidine ring, pyrrolidine ring, piperidine ring,piperazine ring, morpholine ring, 2-azetidinone ring, 2-pyrrolidinonering, 2-piperidinone ring, 2-piperazinone ring or 3-morpholine ring,each of which may be substituted with one to three groups which are thesame as or different from each other selected from: (1) a lower alkylgroup which may be substituted, (2) a lower alkenyl group which may besubstituted, (3) a lower alkynyl group which may be substituted, (4) alower alkoxy group which may be substituted, (5) an oxo group, (6) anitrile group, (7) an alkylenedioxy group, (8) a hydroxyl group, (9) ahalogen atom, (10) an amino group which may be substituted, (11) anacylamino group, (12) a carbamoyl group which may be substituted, (13) acarbamoyloxy group which may be substituted, (14) a carboxyl group, (15)an acyl group, (16) an acyloxy group, (17) an alkoxycarbonyloxy group;and A represents a group having any of the following structuralformulae:

 (wherein R³ and R⁴ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring; R⁵ and R⁶ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring; R⁷ represents a hydrogen atom, an optionally substituted C₁₋₆alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or anoptionally substituted amino group; R⁸ represents a hydrogen atom, ahydroxyl group, an alkoxy group, a halogen atom or an optionallysubstituted amino group, B¹ represents an optionally substituted carbonatom, or an optionally substituted nitrogen atom, oxygen atom or sulfuratom; B² represents an optionally substituted carbon atom or nitrogenatom; a and b represent an integer of 0 to 4, provided that a+b is aninteger of 0 to 4, c represents 0 or 1; and

 represents a single bond or a double bond, provided that when c is 1 inwhich A is a quinuclidine having R⁸ represented by

 the case where R⁸ is a hydrogen atom or a hydroxyl group; Arl is anaromatic heterocycle; and W is one of (1) to (3), (6) to (11) and (16)to (19) are excluded).
 5. The compound according to claim 1, a saltthereof or a hydrate of them, wherein Arl preferably represents abenzene ring, pyridine ring, pyrimidine ring or thiazole ring, each ofwhich may be substituted with a lower alkyl group, a halogen atom or analkoxy group; W preferably represents a chain expressed by (1)optionally substituted —CH₂—CH₂—, (2) optionally substituted —CH═CH—,(3) —C≡C—, (4) an optionally substituted phenylene group, (5) a singlebond, (13) —(CH₂)_(m)—O— (where m represents an integer of 0 to 5), (14)—O—CH₂—CR²═, or (15) —O—CH₂—CHR²— (where R² represents a hydrogen atom,an alkyl group or a halogen atom); R¹ represents an optionallysubstituted vinyl group, a benzene ring which may be substituted or athiophene ring which may be substituted; n is an integer of 0 to 2; CyArepresents an azetidine ring, pyrrolidine ring, piperidine ring,piperazine ring, morpholine ring, 2-azetidinone ring, 2-pyrrolidinonering, 2-piperidinone ring, 2-piperazinone ring or 3-morpholine ring,each of which may be substituted with one to three groups which are thesame as or different from each other and selected from: (1) a loweralkyl group which may be substituted, (2) a lower alkenyl group whichmay be substituted, (3) a lower alkynyl group which may be substituted,(4) a lower alkoxy group which may be substituted, (5) an oxo group, (6)a nitrile group, (7) an alkylenedioxy group, (8) a hydroxyl group, (9) ahalogen atom, (10) an amino group which may be substituted, (11) anacylamino group, (12) a carbamoyl group which may be substituted, (13) acarbamoyloxy group which may be substituted, (14) a carboxyl group, (15)an acyl group, (16) an acyloxy group, and (17) an alkoxycarbonyloxygroup; and A represents a group having any of the following structuralformulae:

 (wherein R³ and R⁴ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring; R⁵ and R⁶ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring; R⁷ represents a hydrogen atom, an optionally substituted C₁₋₆alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or anoptionally substituted amino group; R⁸ represents a hydrogen atom, ahydroxyl group, an alkoxy group, a halogen atom or an optionallysubstituted amino group, B¹ represents an optionally substituted carbonatom, or an optionally substituted nitrogen atom, oxygen atom or sulfuratom; B² represents an optionally substituted carbon atom or nitrogenatom; a and b represent an integer of 0 to 4, provided that a+b is aninteger of 0 to 4, c represents 0 or 1; and

 represents a single bond or a double bond, provided that when c is 1 inwhich A is a quinuclidine having R⁸ represented by

 the case where R⁸ is a hydrogen atom or a hydroxyl group; Arl is anaromatic heterocycle; and W is one of (1) to (3), (6) to (11) and (16)to (19) are excluded).
 6. The compound according to claim 1, a saltthereof or a hydrate of them, wherein Arl preferably represents abenzene ring, pyridine ring, pyrimidine ring or thiazole ring, each ofwhich may be substituted with a lower alkyl group, a halogen atom or analkoxy group; W preferably represents a chain expressed by (1)optionally substituted —CH₂—CH₂—, (2) optionally substituted —CH═CH—,(3) —C≡C—, (4) an optionally substituted phenylene group, (5) a singlebond, (13) —(CH₂)_(m)—O— (where m represents an integer of 0 to 5), (14)—O—CH₂—CR²═, or (15) —O—CH₂—CHR²— (where R² represents a hydrogen atom,an alkyl group or a halogen atom); CyA preferably represents anazetidine ring, pyrrolidine ring, piperidine ring, piperazine ring,morpholine ring, 2-azetidinone ring, 2-pyrrolidinone ring,2-piperidinone ring, 2-piperazinone ring or 3-morpholine ring, each ofwhich may be substituted with one to three groups which are the same asor different from each other selected from: (1) a lower alkyl groupwhich may be substituted, (4) a lower alkoxy group which may besubstituted, (5) an oxo group, (7) an alkylenedioxy group, (8) ahydroxyl group, and (9) a halogen atom; R¹ represents an optionallysubstituted vinyl group, a benzene ring which may be substituted or athiophene ring which may be substituted; n is an integer of 0 to 2; andA represents a group having any of the following structural formulae:

 (wherein R³ and R⁴ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring; R⁵ and R⁶ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring; R⁷ represents a hydrogen atom, an optionally substituted C₁₋₆alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or anoptionally substituted amino group; R⁸ represents a hydrogen atom, ahydroxyl group, an alkoxy group, a halogen atom or an optionallysubstituted amino group, B¹ represents an optionally substituted carbonatom, or an optionally substituted nitrogen atom, oxygen atom or sulfuratom; B² represents an optionally substituted carbon atom or nitrogenatom; a and b represent an integer of 0 to 4, provided that a+b is aninteger of 0 to 4, c represents 0 or 1; and

 represents a single bond or a double bond, provided that when c is 1 inwhich A is a quinuclidine having R⁸ represented by

 the case where R⁸ is a hydrogen atom or a hydroxyl group; Arl is anaromatic heterocycle; and W is one of (1) to (3), (6) to (11) and (16)to (19) are excluded).
 7. The compound according to claim 1, a saltthereof or a hydrate of them, wherein Arl preferably represents abenzene ring, pyridine ring, pyrimidine ring or thiazole ring, each ofwhich may be substituted with a lower alkyl group, a halogen atom or analkoxy group; W preferably represents a chain expressed by (1)optionally substituted —CH₂—CH₂—, (2) optionally substituted —CH═CH—,(3) —C═C—, (4) an optionally substituted phenylene group, (5) a singlebond, (13) —(CH₂)_(m)—O— (where m represents an integer of 0 to 5), (14)—O—CH₂—CR²═, or (15) —O—CH₂—CHR²— (where R² represents a hydrogen atom,an alkyl group or a halogen atom); CyA represents an azetidine ring,pyrrolidine ring, piperidine ring, piperazine ring, morpholine ring,2-azetidinone ring, 2-pyrrolidinone ring, 2-piperidinone ring,2-piperazinone ring or 3-morpholine ring, each of which may besubstituted with one to three groups which are the same as or differentfrom each other and selected from: (1) a lower alkyl group which may besubstituted, (4) a lower alkoxy group which may be substituted, (5) anoxo group, (7) an alkylenedioxy group, (8) a hydroxyl group, and (9) ahalogen atom; R¹ represents a benzene ring which may be substituted; nis an integer of 0 to 2; and A represents a group having any of thefollowing structural formulae:

 (wherein R³ and R⁴ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring; R⁵ and R⁶are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring; R⁷ represents a hydrogen atom, an optionally substituted C₁₋₆alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or anoptionally substituted amino group; R⁸ represents a hydrogen atom, ahydroxyl group, an alkoxy group, a halogen atom or an optionallysubstituted amino group, B¹ represents an optionally substituted carbonatom, or an optionally substituted nitrogen atom, oxygen atom or sulfuratom; B² represents an optionally substituted carbon atom or nitrogenatom; a and b represent an integer of 0 to 4, provided that a+b is aninteger of 0 to 4, c represents 0 or 1; and

 represents a single bond or a double bond, provided that when c is 1 inwhich A is a quinuclidine having R⁸ represented by

 the case where R⁸ is a hydrogen atom or a hydroxyl group; Arl is anaromatic heterocycle; and W is one of (1) to (3), (6) to (11) and (16)to (19) are excluded).
 8. A compound selected from the group consistingof:3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynyl-3-piperidinol;3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynyl-1-methyl-3-piperidinol;4-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]-1-methyl-4-piperidinol;4-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]-1-methyl-1,2,3,6-tetrahydropyridine;3-[3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]propyloxy]pyrrolidine;1-[2-benzyl-6-[(3R,4S)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynylcyclohexylamine;1-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynylcyclohexylamine;1-[2-benzyl-6-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinon-1-yl]-3-pyridyl]ethynylcyclohexylamine;1-(2-benzyl-6-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinon-1-yl]-3-pyridyl]ethynylcyclohexylamine;1-[1-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynylcyclohexyl]piperidine;1-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynyl-N-methylcyclohexylamine;2-[[1-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynylcyclohexyl]amino]ethanol;3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]-1,1-diethyl-2-propynylamine;2-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynylbicyclo[2.2.1]heptan-2-ol;(3R)-3-[2-benzyl-4-(2-pyrrolidinon-1-yl)phenyl]ethynyl-3-quinuclidinol;(3R)-3-[2-benzyl-4-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinon-1-yl)phenyl]ethylnyl-3-quinuclidinol;(3R)-3-[2-benzyl-4-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinon-1-yl]phenyl]ethynyl-3-quinuclidinol;(3R)-3-[2-benzyl-4-[(3R,4S)-3,4-dimethoxypyrrolidin-1-yl)phenyl]ethynyl-3-quinuclidinol;(3R)-3-[2-benzyl-4-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]phenyl]ethynyl-3-quinuclidinol;(3R)-3-[2-benzyl-4-[cis-3-hydroxy-4-methoxypyrrolidin-1-yl]phenyl]ethynyl-3-quinuclidinol;(3R)-3-[2-benzyl-4-[trans-3-hydroxy-4-methoxypyrrolidin-1-yl]phenyl]ethynyl-3-quinuclidinol;3-[4-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]phenyl]-3-quinuclidinol;(E)-3-[2-[2-benzyl-6-(2-pyrrolidinon-1-yl)pyridin-3-yloxy]-1-fluoroethynylidene]quinuclidine;1-[2-benzyl-6-(3,3-ethylenedioxypyrrolidin-1-yl]-3-pyridyl]ethynylcyclohexylamine;1-[2-benzyl-6-(4-methoxypiperidino)-3-pyridyl]ethynylcyclohexylamine;4-[2-benzyl-6-[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]-3pyridyl]ethynyl-exo-1-azaadamantan-4-ol;and4-[2-benzyl-6-[(3R,4R)-3,4-dimethoxypyrrolidin-1-yl]-3-pyridyl]ethynyl-endo-1-azaadamantan-4-ol,a salt thereof or a hydrate of them.
 9. A pharmaceutical compositioncomprising a compound (I) represented by the formula:

(wherein R¹ represents an optionally substituted vinyl group or anaromatic ring which may be substituted; n is an integer of 0 to 2; X, Y,and Z are the same as or different from each other and each representsan optionally substituted carbon atom, or an optionally substitutednitrogen atom, sulfur atom or oxygen atom, and Y may represent a singlebond and when Y represents the single bond, the ring to which X, Y and Zbelong is a 5-membered; CyA represents a 5- to 14 membered non-aromaticcyclic amino group or non-aromatic cyclic amido group, each of which maybe substituted, and the non-aromatic cyclic amino group or thenon-aromatic cyclic amido group may contain an oxygen atom or a sulfuratom; W represents a chain expressed by (1) optionally substituted—CH₂—CH₂—, (2) optionally substituted —CH═CH—, (3) —C═C—, (4) anoptionally substituted phenylene group, (5) a single bond, (6) —NH—CO—,(7) —CO—NH—, (8) —NH—CH₂—, (9) —CH₂—NH—, (10) —CH₂—CO—, (11) —CO—CH₂—,(12) —O—(CH₂)_(m)—, (13) —(CH₂)_(m)—O— (where m represents an integer of0 to 5) (14) —O—CH₂—CR²═, (15) —O—CH₂—CHR²— (where R² represents ahydrogen atom, a C₁₋₆ alkyl group, or a halogen atom), (16) —NH—S(O)₁—,(17) —S(O)₁—NH—, (18) —CH₂—S(O)₁— or (19) —S(O)₁—CH₂— (where 1represents 0, 1, or 2); and A represents a group having any of thefollowing structural formulae:

 (wherein R³ and R⁴ are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring; R⁵ and R⁶are independent of each other and each represents ahydrogen atom or an optionally substituted C₁₋₆ alkyl group, or combinethrough a carbon chain optionally containing a heteroatom to form aring; R⁷ represents a hydrogen atom, an optionally substituted C₁₋₆alkyl group, a hydroxyl group, an alkoxy group, a halogen atom or anoptionally substituted amino group; R⁸ represents a hydrogen atom, ahydroxyl group, an alkoxy group, a halogen atom or an optionallysubstituted amino group, B¹ represents an optionally substituted carbonatom, or an optionally substituted nitrogen atom, oxygen atom or sulfuratom; B² represents an optionally substituted carbon atom or nitrogenatom; a and b represent an integer of 0 to 4, provided that a+b is aninteger of 0 to 4, c represents 0 or 1; and

 represents a single bond or a double bond, provided that when c is 1 inwhich A is a quinuclidine having R⁸ represented by

 the case where R⁸ is a hydrogen atom or a hydroxyl group; Arl is anaromatic heterocycle; and W is one of (1) to (3), (6) to (11) and (16)to (19) are excluded)), a salt thereof or a hydrate of them, and apreparation carrier.
 10. A pharmaceutical composition according to claim9 as an agent for preventing or treating a disease against whichsqualene synthase inhibition is efficacious.
 11. A cholesterolbiosynthesis inhibitor comprising the compound according to any one ofclaims 1 to 8, a salt thereof or a hydrate of them.
 12. A triglyceridebiosynthesis inhibitor comprising the compound according to any one ofclaims 1 to 8, a salt thereof or a hydrate of them.
 13. An agent forpreventing or treating hyperlipidemia, which comprises the compoundaccording to any one of claims 1 to 8, a salt thereof or a hydrate ofthem.
 14. An agent for preventing or treating arterial sclerosisdiseases or is chemic heart diseases, which comprises the compoundaccording to any one of claims 1 to 8, a salt thereof or a hydrate ofthem.
 15. An agent for preventing or treating hypertension, coronarydiseases, cerebrovascular diseases, aortic diseases, peripheral arterialdiseases, angina pectoris, acute coronary syndromes or cardiacinfarction, which comprises the compound according to any one of claims1 to 8, a salt thereof or a hydrate of them.
 16. A method of preventingor treating a disease against which squalene synthase inhibition isefficacious, by administering a pharmaceutically effective amount of thecompound according to claim 1, a salt thereof or a hydrate of them to apatient.
 17. Use of the compound according to claim 1, a salt thereof ora hydrate of them, for producing an agent for preventing or treating adisease against which squalene synthase inhibition is efficacious.
 18. Amethod of preventing or treating a disease against which cholesterolbiosynthesis inhibition is efficacious, a disease against whichtriglyceride biosynthesis inhibition is efficacious, hyperlipidemia,arterial sclerosis diseases, ischemic heart diseases, hypertension,coronary diseases, cerebrovascular diseases, aortic diseases, peripheralarterial diseases, angina pectoris, acute coronary syndromes or cardiacinfarction, by administering a pharmaceutically effective amount of thecompound according to claim 1, a salt thereof or a hydrate of them to apatient.
 19. Use of the compound according to claim 1, a salt thereof ora hydrate of them, for producing an agent for preventing or treating adisease against which cholesterol biosynthesis inhibition isefficacious, a disease against which triglyceride biosynthesisinhibition is efficacious, hyperlipidemia, arterial sclerosis diseases,ischemic heart diseases, hypertension, coronary diseases,cerebrovascular diseases, aortic diseases, peripheral arterial diseases,angina pectoris, acute coronary syndromes or cardiac infarction.